Angiotensin II antagonists incorporating a substituted thiophene or furan

ABSTRACT

Substituted heterocycles attached through a methylene bridge to novel substituted phenyl thiophene or phenyl furan derivative of the Formula I are useful as angiotensin II antagonists. ##STR1##

BACKGROUND OF THE INVENTION

The present application is a continuation in part of U.S. Ser. No.07/691,911 filed on Apr. 26, 1991 now abandoned.

The Renin-angiotensin system (RAS) plays a central role in theregulation of normal blood pressure and seems to be critically involvedin hypertension development and maintenance as well as congestive heartfailure. Angiotensin II (A II), is an octapeptide hormone producedmainly in the blood during the cleavage of angiotensin I by angiotensinconverting enzyme (ACE) localized on the endothelium of blood vessels oflung, kidney, and many other organs. It is the end product of therenin-angiotensin system (RAS) and is a powerful arterialvasoconstrictor that exerts its action by interacting with specificreceptors present on cell membranes. One of the possible modes ofcontrolling the RAS is antiotensin II receptor antagonism. Severalpeptide analogs of A II are known to inhibit the effect of this hormoneby competitively blocking the receptors, but their experimental andclinical applications have been limited by partial agonist activity andlack of oral absorption [M. Antonaccio. Clin. Exp. Hypertens, A4, 27-46(1982); D. H. P. Streeten and G. H. Anderson, Jr.--Handbook ofHypertension, Clinical Pharmacology of Antihypertensive Drugs, ed. A. E.Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, TheNetherlands, 1984].

Recently, several non-peptide compounds have been described as A IIantagonists. Illustrative of such compounds are those disclosed in U.S.Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804 andin European Patent Applications 028,834; 234,637; 253,310; and 291,969;and articles by A. T. Chiu, et al. [Eur. J. Pharm. Exp. Therap, 157,13-21 (1988)] and by P. C. Wong, et al. [J. Pharm. Exp. Therap, 247, 1-7(1988)]. All of the U.S. Patents, European Patent Applications 028,834and 253,310 and the two articles disclose substituted imidazolecompounds which are generally bonded through a lower alkyl bridge to asubstituted phenyl. European Patent Application 245,637 disclosesderivatives of4,5,6,7-tetrahydro-2H-imidazo[4,5-c]-pyridine-6-carboxylic acid andanalogs thereof as antihypertensive agents.

None of the compounds disclosed in any U.S. Patent, EuropeanApplications or literature publication are of the type containingsubstituted heterocycles bonded through an alkyl bridge to a novelsubstituted phenyl thiophene or phenyl furan of the type disclosedherein. The quinazolin-4(1H)-ones, triazolinones, triazolinimines, andpyrimidinones have been disclosed in earlier U.S. Patent applicationsfocusing on the heterocyclic fragment of the antagonist design. The Ser.Nos. of these applications are 351,508; 358,971; 375,655; 360,673;375,217; and 386,328. A related application U.S. Ser. No. 675,371, filedMar. 26, 1991, discloses 6-membered ring fused imidazoles incorporatinga thiophene or furan moiety.

BRIEF DESCRIPTION OF THE INVENTION

This invention is directed to substituted heterocycles attached througha methylene bridge to novel substituted phenylthiophene or phenylfuranderivative to give compounds of the Formula I, which are angiotensin IIantagonists and are useful in the treatment of hypertension andcongestive heart failure. The compounds of the invention are useful asocular antihypertensives.

Specifically, the compounds of this invention contain a heterocyclicmoiety which is substituted at the specified positions and to which ismethylene bridge connecting a novel substituted phenylthiophene orphenylfuran group as defined by the lower portion of Formula I, isattached. Additionally, pharmaceutically acceptable compositions ofthese novel compounds, as the sole therapeutically active ingredient andin combination with diuretics and other antihypertensive agents,including beta blockers, angiotensin converting enzyme inhibitors,calcium channel blockers or a combination thereof are disclosed andclaimed. Further, methods of treating hypertension and congestive heartfailure are described and claimed.

The compounds of this invention have central nervous system (CNS)activity. They are useful in the treatment of cognitive dysfunctionsincluding Alzheimer's disease, amnesia and senile dementia. Thesecompounds also have anxiolytic and antidepressant properties and aretherefore, useful in the relief of symptoms of anxiety and tension andin the treatment of patients with depressed or dysphoric mental states.

In addition, these compounds exhibit antidopaminergic properties and arethus useful to treat disorders that involve dopamine dysfunction such asschizophrenia. The compounds of this invention are especially useful inthe treatment of these conditions in patients who are also hypertensiveor have a congestive heart failure condition.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of the general Formula I: ##STR2##and the heterocycle is specifically defined as: ##STR3## R¹ is: (a) (C₁-C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which isunsubstituted or substituted with a substituent selected from the groupconsisting of:

i) aryl as defined below,

ii) (C₃ -C₇)-cycloalkyl,

iii) Cl, Br, I, F,

iv) OH,

v) NH₂,

vi) NH(C₁ -C₄)-alkyl,

vii) N[(C₁ -C₄)-alkyl]₂,

viii) NHSO₂ R²,

ix) CF₃,

x) COOR², or

xi) SO₂ NHR^(2a) ;

(b) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstitutedor substituted with 1 or 2 substituents selected from the groupconsisting of:

i) Br, I, Cl, F,

ii) (C₁ -C₄)-alkyl,

iii) (C₁ -C₄)-alkoxy,

iv) NO₂

v) CF₃

vi) SO₂ NR^(2a) R^(2a),

vii) (C₁ -C₄)-alkylthio,

viii) hydroxy,

ix) amino,

x) (C₃ -C₇)-cycloalkyl, or

xi) (C₃ -C₁₀)-alkenyl;

(c) heteroaryl, wherein heteroaryl is defined as a 5- or 6-memberedheteroaromatic moiety, which can contain one or two members selectedfrom the group consisting of N, O, S and wherein the heteroaryl isunsubstituted, monosubstituted or disubstituted with substituentsselected from the group consisting of:

i) Cl, Br, I, or F,

ii) OH,

iii) SH,

iv) NO₂,

v) (C₁ -C₄)-alkyl,

vi) (C₂ -C₄)-alkenyl,

vii) (C₂ -C₄)-alkynyl,

viii) (C₁ -C₄)-alkoxy, or

ix) CF₃, or

(d) (C₁ -C₄)-polyfluoroalkyl;

E is:

(a) a single bond,

(b) --S(O)_(n) (CH₂)_(s) --, or

(c) --O--;

n is 0 to 2;

s is 0 to 5;

J¹ is (a)--C(═M)--, (b) J¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b) or (c) J¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom not at J¹, substituted withR^(7a), R^(8a) l and R^(8b) ;

K¹ is (a)--C(═M)--, (b) K¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b), or (c) K¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom, substituted on the carbonatoms with R^(7a), R^(8a) and R^(8b) ;

one of a¹ or b¹ is a double bond in structures Ia provided that when J¹is --C(═M)-- then b¹ is a double bond and when K¹ is --C(═M)-- then a¹is a double bond;

L is the point of attachment of the 6-membered fused aromatic ringoptionally containing one nitrogen atom;

J² is (a)--C(═M)--, or (b) --C(R¹⁷)--;

K² is (a)--C(═M)--, or (b)--C(R¹⁷)--, provided that one and only one ofJ² and K² is --C(═M)--;

one of a² or b² is a double bond in structure Ic provided that when J²is --C(═M)-- then b² is a double bond and when K² is --C(═M)-- then a²is a double bond.

M is O, S or NR¹⁵ ;

R² is:

(a) H, or

(b) (C₁ -C₆)-alkyl;

R^(2a) is:

(a) R²,

(b) CH₂ -aryl, or

(c) aryl;

R^(2b) is:

(a) R^(2a), or

(b) C₃ -C₇ cycloalkyl;

R^(2c) is:

(a) --SO₂ --(C₁ -C₆)-alkyl,

(b) --CO--(C₁ -C₆)-alkyl,

(c) --SO₂ --(C₃ -C₆)-cycloalkyl,

(d) --CO--(C₃ -C₆)-cycloalkyl,

(e) --SO₂ --(C₁ -C₄)-polyfluoroalkyl,

(f) --CO-aryl,

(g) --CO-polyfluoroaryl,

(h) --CO--(2- or 3-thienyl),

(i) --SO₂ --(2- or 3-thienyl),

(j) --CO--(2-, 3- or 4-pyridyl),

(k) --CONH--(C₁ -C₆)-alkyl,

(l) --CON[(C₁ -C₆)alkyl]₂,

(m) --CO₂ -(C₁ -C₆)-alkyl, or

(n) --CO₂ --(C₃ -C₆)cycloalkyl;

R^(7a) and R^(7b) are independently

(a) H,

(b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl,

(c) Cl, Br, I, F,

(d) CF₃, or

(e) when R^(7a) and R^(7b) are bonded to adjacent carbon atoms, they canbe joined to form a phenyl ring;

R^(8a) and R^(8b) are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl,

(c) heteroaryl-(C₁ -C₄)-alkyl,

(d) (C₁ -C₆)-alkyl, which is unsubstituted or substituted with asubstituent selected from the group consisting of: --CON(R^(2a))₂,-heteroaryl, --S(O)_(n) R²¹, -tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂NH-heteroaryl, --SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN,--NR^(2a) COOR²¹, --OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁ -C₄)-dialkylamino, --COOR^(2a),--CONHR^(2a), --O--COR^(2a), aryl, or ##STR4## (e) --CO-aryl, (f) (C₃-C₇)-cycloalkyl,

(g) Cl, Br, I, F,

(h) --OH,

(i) --OR²¹,

(j) --SH,

(k) --S(O)_(n) --(C₁ -C₄)-alkyl,

(l) --COR^(2a),

(m) --CO₂ H,

(n) --SO₃ H,

(o) --NR^(2a) R²¹,

(p) --NR^(2a) COR²¹,

(q) --NR^(2a) COOR²¹,

(r) --SO₂ NHR^(2a),

(s) --SO₂ NR² R^(2a),

(t) --NO₂,

(u) --NHSO₂ CF₃,

(v) --CONR^(2a) R²¹,

(w) --(C₁ -C₄)-polyfluoroalkyl,

(x) --COOR²,

(y) --SO₃ H,

(z) --N(R^(2a))SO₂ R²¹,

(aa) --NR^(2a) CONR^(2b) R²¹,

(bb) --OC(═O)NR²¹ R^(2a),

(cc) -aryl,

(dd) --NHSO₂ CF₃,

(ee) --SO₂ NH-heteroaryl,

(ff) --SO₂ NHCOR²¹,

(gg) --CONHSO₂ R²¹,

(hh) --PO(OR²)₂,

(ii) -tetrazol-5-yl,

(jj) --CONH(tetrazol-5-yl),

(kk) --SO₂ NHCN,

(ll) -heteroaryl, ##STR5## --X¹ --X² --X³ --X⁴ -- is: (a) --Y--CR¹¹--CR¹² --CZ--,

(b) --CR¹¹ --Y--CR¹² --CZ--,

(c) --CR¹¹ --CR¹² --Y--CZ--,

(d) --Y--CR¹¹ --CZ--CR¹² --,

(e) --CR¹¹ --Y--CZ--CR¹² --, or

(f) --CR¹¹ --CR¹² --CZ--Y--;

Y is: O, S, SO, or SO₂ ;

R⁹ and R¹⁰ are each independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) (C₁ -C₆)-alkyl,

(e) (C₁ -C₆)-acyloxy,

(f) (C₃ -C₆)-cycloalkyl,

(g) (C₁ -C₆)-alkoxy,

(h) --NHSO₂ R^(2a),

(i) hydroxy-(C₁ -C₄)-alkyl,

(j) (C₁ -C₄)-alkyl-aryl,

(k) S(O)_(n) --(C₁ -C₄)-alkyl,

(n) NR^(2a) R^(2a),

(q) CF₃,

(r) --SO₂ NHR^(2a),

(s) furyl,

(t) aryl, wherein aryl is phenyl or naphthyl, unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, NO₂, CF₃,(C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--CO₂ H, or --CO₂ --(C₁ -C₄)-alkyl, or

(u) when R⁹ and R¹⁰ are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

R¹¹ and R¹² are independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) NH₂,

(e) NH[(C₁ -C₄)-alkyl],

(f) N[(C₁ -C₄)-alkyl]₂,

(g) SO₂ NHR^(2a),

(h) CF₃,

(i) (C₁ -C₇)-alkyl,

(j) (C₁ -C₆)-alkoxy, or

(k) (C₃ -C₇)-cycloalkyl,

(l) when R¹¹ and R¹² are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

(m) O(CH₂)_(n+1) O(CH₂)_(s) CH₃,

(n) (CH₂)_(n+1) O(CH₂)_(s) CH₃,

(o) (CH₂)N(R^(2a))₂,

(p) CH₂ N[CH₂ CH₂ ]₂ O,

(q) (CH₂)_(n) N[CH₂ CH₂ ]₂ CH₂,

(r) CH(OR^(2a))[(C₁ -C₇)-alkyl],

(s) CHO,

(t) CO₂ R^(2a),

(u) CH═CH--R^(2a),

(v) CH₂ CR^(2a) ═C(R^(2a))₂, or

(w) (CH₂)_(n) NCOR^(2a) ;

(x) (CH₂)_(n) aryl, or

(y) CH(R^(2a))₂ ;

Z is:

(a) --CO₂ R^(2a),

(b) --SO₃ R¹³,

(c) --NHSO₂ CF₃,

(d) --PO(OR¹³)₂,

(e) --SO₂ NHR^(2a),

(f) --CONHOR¹³, ##STR6## (h) --CN, (i) --SO₂ NH-heteroaryl, whereinheteroaryl is an unsubstituted, monosubstituted or disubstituted five orsix membered aromatic ring which can contain from 1 to 3 heteroatomsselected from the group consisting of O, N or S and wherein thesubstituents are members selected from the group consisting of: --OH,--SH, --(C₁ -C₄)-alkyl, --(C₁ -C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂,--CO₂ H, --CO₂ --(C₁ -C₄)-alkyl, --NH₂, NH[(C₁ -C₄)-akyl] and --N[(C₁-C₄)-alkyl]₂,

(j) --CH₂ SO₂ NH-heteroaryl,

(k) --SO₂ NH--CO--R¹⁴,

(l) --CH₂ SO₂ NH--CO--R¹⁴,

(m) --CONH--SO₂ R¹⁴,

(n) --CH₂ CONH--SO₂ R¹⁴,

(o) --NHSO₂ NHCO--R¹⁴,

(p) --NHCONHSO₂ --R¹⁴, ##STR7## (t) --CONHNHSO₂ CF₃, ##STR8## R¹⁴ is (a)aryl,

(b) heteroaryl,

(c) (C₃ -C₇)-cycloalkyl, or

(d) (C₁ -C₇)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: aryl, heteroaryl, --OH, --SH, (C₁-C₄)-alkyl, --(C₁ -C₄)-alkoxy, --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I,--NO₂, --CO₂ H, CO₂ --(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃H or PO(OH)(O--(C₁ -C₄)-alkyl);

(e) (C₁ -C₇)-alkoxy,

(f) O(CH₂)_(n+1) O(CH₂)_(s) CH₃,

(g) (CH₂)_(n+1) O(CH₂)_(s) CH₃, or

(h) CH(R^(2a))₂ ;

(i) (C₁ -C₆)-polyfluoroalkyl, or

(j) --NH--(C₁ -C₆)-alkyl;

R¹⁵ is

(a) H,

(b) aryl, which is unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of: Cl, Br, I, F --O--(C₁ -C₄)-alkyl,(C₁ -C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl,--OH, --NH₂, (C₃ -C₇)-cycloakyl, (C₃ -C₁₀)-alkenyl;

(c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of: aryl, (C₃ -C₇)-cycloalkyl, Cl, Br, I, F,--OH, --NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or

(d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6membered ring which can contain one or two heteroatoms selected from thegroup consisting of N, O, S, and wherein the substituents are membersselected from the group consisting of --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkoxy, --CF₃, Cl, Br, I, F, or NO₂ ;

R¹⁶ is

(a) (C₁ -C₁₀)-alkyl,

(b) substituted (C₁ -C₁₀)-alkyl in which one or two substituent(s)selected from the group consisting of:

(1) I, Br, Cl, F,

(2) hydroxy,

(3) (C₁ -C₁₀)-alkoxy,

(4) (C₁ -C₅)-alkoxycarbonyl,

(5) (C₁ -C₅)-acyloxy,

(6) (C₃ -C₈)-cycloalkyl,

(7) aryl,

(8) substituted aryl, in which the substituents are V and W,

(9) (C₁ -C₁₀)-alkyl-S(O)_(n),

(10) (C₃ -C₈)-cycloalkyl-S(O)_(n),

(11) phenyl-S(O)_(n),

(12) substituted phenyl-S(O)_(n), in which the substituents are V and W,

(13) oxo,

(14) carboxy,

(15) NR^(2a) R^(2a), or

(16) (C₁ -C₅)alkylaminocarbonyl;

(c) polyfluoro-(C₁ -C₄)-alkyl,

(d) (C₂ -C₁₀)-alkenyl,

(e) (C₂ -C₁₀)-alkynyl,

(f) (C₃ -C₈)-cycloalkyl,

(g) substituted (C₃ -C₈)-cycloalkyl, in which the substituent isselected from:

(1) (C₁ -C₅)-alkyl, or

(2) (C₁ -C₅)-alkoxy;

(h) aryl,

(i) substituted aryl, in which the substituents are V and W,

(j) aryl-(CH₂)_(r) --(M₁)_(z) --(CH₂)_(t) --,

(k) substituted aryl--(CH₂)_(r) --(M₁)_(z) --(CH₂)_(t) -- in which thearyl group is substituted with V and W, ##STR9## (q) --[(C₁-C₄)-alkyl]NR² R²¹, (r) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(s) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(t) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(u) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(v) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(w) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

V and W are each independently selected from:

(a) H,

(b) (C₁ -C₅)-alkoxy,

(c) (C₁ -C₅)-alkyl,

(d) hydroxy,

(e) (C₁ -C₅)-alkyl-S(O)_(n),

(f) --CN,

(g) --NO₂,

(h) --NR² R^(2a),

(i) (C₁ -C₅)-acyl-NR² R^(2a),

(j) --CO₂ R^(2a),

(k) (C₁ -C₅)-alkyl-carbonyl,

(l) CF₃,

(m) I, Br, Cl, F,

(n) hydroxy-(C₁ -C₄)-alkyl-,

(o) carboxy-(C₁ -C₄)-alkyl-,

(p) -tetrazol-5-yl,

(q) --NH--SO₂ CF₃, or

(r) aryl;

M₁ is M or --C(O)--;

z is 0 or 1;

r and t are 0 to 2;

R¹⁷ and R¹⁸ are each independently selected from:

(a) H,

(b) aryl-(C₁ -C₄)-alkyl-,

(c) heteroaryl-(C₁ -C₄)-alkyl-,

(d) (C₁ -C₄)-alkyl unsubstituted or substituted with a substituentselected from the group consisting of --OH, --NH₂, guanidino,

(C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio,

(C₁ -C₄)-alkylamino,

(C₁ -C₄)-dialkylamino, --COOR^(2a),

CONHR^(2a), --O--COR^(2a), CF₃ ;

(e) (C₁ -C₄)-alkenyl,

(f) --CO-aryl,

(g) (C₃ -C₇)-cycloalkyl,

(h) Cl, Br, I, F,

(i) --OH,

(j) --O--(C₁ -C₄)-alkyl,

(k) --(C₁ -C₄)-polyfluoroalkyl,

(l) --SH,

(m) --S(O)_(n) --(C₁ -C₄)-alkyl,

(n) --CHO,

(o) --CO₂ R^(2a),

(p) --SO₃ H,

(q) --NH₂,

(r) --NH[(C₁ -C₄)-alkyl],

(s) --N[(C₁ -C₄)-alkyl]₂,

(t) --NHCO₂ --(C₁ -C₄)-alkyl,

(u) --SO₂ NR² R^(2a),

(v) --CH₂ OCOR^(2a),

(w) --NH--SO₂ --(C₁ -C₄)-alkyl,

(x) 5 or 6 membered saturated heterocycle containing one nitrogen atomand optionally containing one other heteroatom selected from N, O, or S,such as pyrrolidine, morpholine, or piperazine,

(y) aryl,

(z) heteroaryl, wherein heteroaryl is a 5 or 6 membered aromatic ringcontaining one or two heteroatoms selected from the group consisting ofO, N, or S,

(aa) tetrazol-5-yl,

(bb) --[(C₁ -C₄)-alkyl]NR² R²¹,

(cc) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(dd) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(ee) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(ff) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(gg) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(hh) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

R¹⁹ is:

(a) H,

(b) (C₁ -C₆)-alkyl,

(c) (C₂ -C₄)-alkenyl,

(d) (C₁ -C₄)-alkoxy, or

(e) benzyl, wherein the phenyl is unsubstituted or substituted with asubstituent selected from the group consisting of: --NO₂, --NH₂, --OH or--OCH₃ ;

R²⁰ is --CN, --NO₂, --CO₂ R^(2a), or --CF₃ ; and

R²¹ is:

(a) aryl, unsubstituted or substituted with a substituent selected fromCl, Br, F or I, or

(b) (C₁ -C₄)-alkyl is unsubstituted or substituted with:

i) NH₂,

ii) NH[(C₁ -C₄)-alkyl],

iii) N[(C₁ -C₄)-alkyl]₂,

iv) CO₂ H,

v) CO₂ (C₁ -C₄)-alkyl,

vi) OH,

vii) SO₃ H, or

viii) SO₂ NH₂,

(c) heteroaryl, or

(d) (C₃ -C₇) cycloalkyl;

or a pharmaceutically acceptable salt thereof.

Wherein an embodiment of the invention is when:

R¹ is:

(a) (C₁ -C₆)-alkyl or (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with a substituent selected from thegroup consisting of:

i) (C₁ -C₄)-alkylthio,

ii) (C₁ -C₄)-alkoxy,

iii) CF₃,

iv) CF₂ CF₃, or

v) (C₃ -C₅)-cycloalkyl,

(b) polyfluoro-(C₁ -C₄)-alkyl, or

(c) (C₃ -C₅)-cycloalkyl;

E is:

(a) single bond,

(b) --S--, or

(c) --O--;

J¹ is (a)--C(═M)--, (b) J¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b) or (c) J¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom not at J¹, substituted withR^(7a), R^(8a) and R^(8b) ;

K¹ is (a)--C(═M)--, or (b) K¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b), or (c) K¹ and L are connected together to form a six-memberedaromatic ring containing one nitrogen atom substituted with R^(7a),R^(8a) and R^(8b) provided that one and only one of J¹ and K¹ is--C(═M)--;

one of a¹ or b¹ is a double bond in structure Ia provided that when J¹is --C(═M)-- then b¹ is a double bond and when K¹ is --C(═M)-- then a¹is a double bond;

L is the point of attachment of the 6-membered fused aromatic ringoptionally containing one nitrogen atom;

J² is (a)--C(═M)--, or (b) --C(R¹⁷)--;

K² is (a)--C(═M)--, or (b)--C(R¹⁷)--, provided that one and only one ofJ² and K² is --C(═M)--;

one of a² or b² is a double bond in structure Ic provided that when J²is --C(═M)-- then b² is a double bond and when K² is --(═M)-- then a² isa double bond.

M is O, S or NR¹⁵ ;

R² is:

(a) H,

(b) (C₁ -C₆)-alkyl;

R^(2a) is:

(a) R²,

(b) CH₂ aryl, or

(c) aryl;

R^(2b) is:

(a) R^(2a), or

(b) C₃ -C₇ cycloalkyl;

R^(2c) is:

(a) --SO₂ --(C₁ -C₆)-alkyl,

(b) --CO--(C₁ -C₆)-alkyl,

(c) --SO₂ --(C₃ -C₆)-cycloalkyl,

(d) --CO--(C₃ -C₆)-cycloalkyl,

(e) --SO₂ --(C₁ -C₄)-polyfluoroalkyl,

(f) --CO-aryl,

(g) --CO-polyfluoroaryl,

(h) --CO-(2- or 3-thienyl),

(i) --SO₂ --(2- or 3-thienyl),

(j) --CO--(2- , 3- or 4-pyridyl),

(k) --CONH--(C₁ -C₆)-alkyl,

(l) --CON[(C₁ -C₆)alkyl]₂,

(m) --CO₂ --(C₁ -C₆)-alkyl, or

(n) --CO₂ --(C₃ -C₆)cycloalkyl;

R^(7a) and R^(7b) are independently

(a) H,

(b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl,

(c) Cl, Br, I, F,

(d) CF₃, or

(e) when R^(7a) and R^(7b) are bonded to adjacent carbon atoms, they canbe joined to form a phenyl ring;

R^(8a) and R^(8b) are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl,

(c) heteroaryl-(C₁ -C₄)-alkyl,

(d) (C₁ -C₆)-alkyl, is unsubstituted or substituted with a substituentselected from the group consisting of: --CON(R^(2a))₂, -heteroaryl,--S(O)_(x) --R²¹, -tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂ NH-heteroaryl,--SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN, --NR^(2a)COOR²¹, --OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁-C₄)-alkylamino, (C₁ -C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a),--O--COR^(2a), aryl, or ##STR10## (e) --CO-aryl, (f) C₃ -C₇)-cycloalkyl,

(g) Cl, Br, I, F,

(h) --OH,

(i) --OR²¹,

(j) --SH,

(k) --S(O)_(n) --(C₁ -C₄)-alkyl,

(l) --COR^(2a),

(m) --CO₂ H,

(n) --SO₃ H,

(o) --NR^(2a) R²¹,

(p) --NR^(2a) COR²¹,

(q) --NR²¹ COOR²¹,

(r) --SO₂ NR^(2a),

(s) --SO₂ NR² R^(2a),

(t) --NO₂,

(u) --NHSO₂ CF₃,

(v) --CONR^(2a) R²¹,

(w) --(C₁ -C₄)-polyfluoroalkyl,

(x) --COOR²,

(y) --SO₃ H,

(z) --N(R^(2a))SO₂ R²¹,

(aa) --NR^(2a) CONR^(2b) R²¹,

(bb) --OC(═)NR²¹ R^(2a),

(cc) -aryl,

(dd) --NHSO₂ CF₃,

(ee) --SO₂ NH-heteroaryl,

(ff) --SO₂ NHCOR²¹,

(gg) --CONHSO₂ R²¹,

(hh) --PO(OR²)₂,

(ii) --tetrazol-5-yl,

(jj) --CONH(tetrazol-5-yl),

(kk) --SO₂ NHCN,

(ll) --heteroaryl, ##STR11## --X¹ --X² --X³ --X⁴ -- is: (a) --Y--CR¹¹--CR¹² --CZ--,

(b) --CR¹¹ --Y--CR¹² --CZ--,

(c) --CR¹¹ --CR¹² --Y--CZ--,

(d) --Y--CR¹¹ --CZ--CR¹² --,

(e) --CR¹¹ --Y--CZ--CR¹² --, or

(f) --CR¹¹ --CR¹² --CZ--Y--;

Y is: O, S, SO, or SO₂ ;

R⁹ and R¹⁰ are each independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) (C₁ -C₆)-alkyl,

(e) (C₁ -C₆)-acyloxy,

(f) (C₃ -C₆)-cycloalkyl,

(g) (C₁ -C₆)-alkoxy,

(h) --NHSO₂ R^(2a),

(i) hydroxy-(C₁ -C₄)alkyl,

(j) (C₁ -C₄)-alkyl-aryl,

(k) S(O)_(n) -(C₁ -C₄)-alkyl,

(n) NR^(2a) R^(2a),

(q) CF₃,

(r) --SO₂ NHR^(2a),

(s) furyl,

(t) aryl, wherein aryl is phenyl or naphthyl, unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, NO₂, CF₃,(C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--CO₂ H, or --CO₂ -(C₁ -C₄ -alkyl, or

(u) when R⁹ and R¹⁰ are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

R¹¹ and R¹² are independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) NH₂,

(e) NH[(C₁ -C₄)-alkyl],

(f) N[(C₁ -C₄)-alkyl]₂,

(g) SO₂ NHR^(2a),

(h) CF₃,

(i) (C.sub. -C₇)-alkyl,

(j) (C₁ -C₆)-alkoxy, or

(k) (C₃ -C₇)-cycloalkyl,

(l) when R¹¹ and R¹² are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

(m) O(CH₂)_(n+1) O(CH₂)_(s) CH₃,

(n) (CH₂)_(n+1) O(CH₂)_(s) CH₃,

(o) (CH₂)N(R^(2a))₂,

(p) (CH₂)_(n) N[CH₂ CH₂ ]₂ X,

(q) (CH₂)_(n) N[CH₂ CH₂ ]₂ CH₂,

(r) CH(OR^(2a))[(C₁ -C₇)-alkyl],

(s) CHO,

(t) CO₂ R^(2a),

(u) CH═CH--R^(2a),

(v) CH₂ CR^(2a) ═C(R^(2a))₂,

(w) (CH₂)_(n) NCOR^(2a),

(x) (CH₂)_(n) aryl, or

(y) CH(R^(2a))₂ ;

Z is:

(a) --CO₂ R^(2a) ;

(b) --NHSO₂ CF₃,

(c) --SO₂ NHR^(2a),

(d) --CN,

(e) --SO₂ NH-heteroaryl, wherein heteroaryl is an unsubstituted,monosubstituted or disubstituted five or six membered aromatic ringwhich can optionally contain from 1 to 3 heteroatoms selected from thegroup consisting of O, N or S and wherein the substituents are membersselected from the group consisting of --OH, --SH, --(C₁ -C₄)-alkyl,--(C₁ -C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --C₁ -C₄-alkyl, --NH₂, NH[(C₁ -C₄)-alkyl] and --N[(C₁ -C₄ -alkyl]₂,

(f) --1H-tetrazol-5-yl,

(g) --CH₂ -1H-tetrazol-5-yl,

(h) --CONH-1H-tetrazol-5-yl, or

(i) --SO₂ HNCOR¹⁴ ;

R¹⁴ is

(a) aryl,

(b) heteroaryl,

(c) (C₃ -C₇)-cycloalkyl, or

(d) (C₁ -C₇)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: aryl, heteroaryl, --OH, --SH, (C₁-C₄)alkyl, --(C₁ -C₄)-alkoxy, --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I,--NO₂, --CO₂ H, CO₂ --(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃H or PO(OH)(O--(C₁ -C₄)-alkyl);

(e) (C₁ -C₇)-alkoxy,

(f) O(CH₂)_(n+1) O(CH₂)_(s) CH₃,

(g) (CH₂)_(n+1) O(CH₂)_(s) CH₃,

(h) CH(R^(2a))₂,

(i) --NH--(C₁ -C₆)-alkyl,

R¹⁵ is:

(a) H,

(b) aryl, is unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of Cl, Br, I, F, --O--(C₁ -C₄)-alkyl,(C₁ -C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl,--OH, --NH₂, (C₃ -C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl;

(c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of: aryl, (C₃ -C₇)-cycloalkyl, Cl, Br, I, F,--OH, --NH₂, --NH[(C₁ -C₄)-alkyl, --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or

(d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6membered ring which contains one or two heteroatoms selected from thegroup consisting of N, O, S, and wherein the substituents are membersselected from the group consisting of --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkyloxy --CF₃, Cl, Br, I, F, or NO₂ ;

R¹⁶ is:

(a) (C₁ -C₁₀)-alkyl,

(b) substituted (C₁ -C₁₀)-alkyl in which one or two substituent(s) is(are) selected from:

(1) hydroxy,

(2) (C₁ -C₅)-alkoxy,

(3) (C₁ -C₅)-alkoxycarbonyl,

(4) phenyl,

(5) carboxy, or

(6) C(═O)NH-(C₁ -C₅)-alkyl;

(c) aryl, or

(d) aryl substituted with V and W;

V and W are selected from:

(a) H,

(b) (C₁ -C₅)-alkoxy,

(c) (C₁ -C₅)-alkyl,

(d) hydroxy,

(e) --CN,

(f) --NO₂,

(g) --NR² R^(2a),

(h) --CO² R^(2a),

(i) --CF₃,

(j) I, Br, Cl, F,

(k) hydroxy-(C₁ -C₄)-alkyl--,

(l) tetrazol-5-yl,

(m) --NH--SO₂ CF₃,

(n) --[(C₁ -C₄)-alkyl]NR² R²¹,

(o) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(p) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(q) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(r) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(s) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(t) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

R¹⁷ and R¹⁸ are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl--,

(c) heteroaryl-(C₁ -C₄)-alkyl--,

(d) (C₁ -C₄)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: --OH, --NH₂, guanidino, (C₁-C₄)alkoxy, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁-C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a), or --O--COR^(2a), CF₃,

(e) (C₁ -C₄)-alkenyl,

(f) --CO--aryl,

(g) (C₃ -C₇)-cycloalkyl,

(h) Cl, Br, I, F,

(i) --OH,

(j) --O--(C₁ -C₄)-alkyl,

(k) --(C₁ -C₄)-polyfluoroalkyl,

(l) --SH,

(m) --S(O)_(n) --(C₁ -C₄)-alkyl,

(n) --CHO,

(o) --CO₂ R^(2a),

(p) --SO₃ H,

(q) --NH₂,

(r) --NH[(C₁ -C₄)-alkyl],

(s) --N[(C₁ -C₄)-alkyl]₂,

(t) --NHCO₂ --(C₁ -C₄)-alkyl,

(u) --SO₂ NR² R^(2a),

(v) --CH₂ OCOR^(2a),

(w) --NH--SO₂ --(C₁ -C₄)-alkyl,

(x) 5 or 6 membered saturated heterocycle containing one nitrogen atomand optionally containing one other heteroatom selected from N, O, or S,such as pyrrolidine, morpholine, or piperazine,

(y) aryl,

(z) heteroaryl, wherein heteroaryl is a 5 or 6 membered aromatic ringcontaining one or two heteroatoms selected from the group consisting ofO, N, or S;

(aa) tetrazol-5-yl, or

(bb) --[(C₁ -C₄)-alkyl]NR² R²¹,

(cc) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(dd) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(ee) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(ff) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(gg) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(hh) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

R²¹ is:

(a) aryl, unsubstituted or substituted with a substituent selected fromCl, Br, F or I, or

(b) (C₁ -C₄)-alkyl which is unsubstituted or substituted with:

i) NH₂,

ii) NH[(C₁ -C₄)-alkyl],

iii) N[(C₁ -C₄)-alkyl]₂,

iv) CO₂ H,

v) CO₂ (C₁ -C₄)-alkyl,

vi) OH,

vii) SO₃ H, or

viii) SO₂ NH₂ ;

(c) heteroaryl, or

(d) C₃ -C₇ cycloalkyl;

or a pharmaceutically acceptable salt thereof.

Wherein another embodiment of the invention is when:

R¹ is:

(a) (C₁ -C₆)-alkyl (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which isunsubstituted or substituted with a substituent selected from the groupconsisting of:

i) (C₁ -C₄)-alkylthio,

ii) (C₁ -C₄)-alkoxy,

iii) CF₃,

iv) CF₂ CF₃, or

v) (C₃ -C₅)-cycloalkyl, or

(b) (C₁ -C₄)-polyfluoroalkyl;

E is a single bond;

J¹ and L are connected together to form a 6-carbon aromatic ringsubstituted with R^(7a), R^(7b), R^(8a) and R^(8b) ; or J¹ and L areconnected together to form a 6 -membered aromatic ring containing onenitrogen atom not at J¹, substituted with R^(7a), R^(8a) and R^(8b) ;

K¹ is --C(═M)--;

a¹ is a double bond;

L is the point of attachment of the 6-membered fused aromatic ringoptionally containing one nitrogen atom;

J² is --C(R¹⁷)--;

K² is --C(═M)--;

a² is a double bond;

M is O, or NR¹⁵ ;

R² is:

(a) H,

(b) (C₁ -C₆)-alkyl, or

(c) (C₁ -C₆)-alkyl;

R^(2a) is:

(a) R²,

(b) benzyl, or

(c) phenyl;

R^(2b) is:

(a) R^(2a), or

(b) C₃ -C₇ cycloalkyl;

R^(2c) is:

(a) --SO₂ --(C₁ -C₆)-alkyl,

(b) --CO--(C₁ -C₆)-alkyl,

(c) --SO₂ --(C₃ -C₆)-cycloalkyl,

(d) --CO--(C₃ -C₆)-cycloalkyl,

(e) --SO₂ --(C₁ -C₄)-polyfluoroalkyl,

(f) --CO-aryl,

(g) --CO-polyfluoroaryl,

(h) --CO--(2- or 3-thienyl),

(i) --SO₂ --(2- or 3-thienyl),

(j) --CO--(2-, or 3- or 4-pyridyl),

(k) --CONH--(C₁ -C₆)-alkyl,

(l) --CON[(C₁ -C₆)alkyl]₂,

(m) --CO₂ --(C₁ -C₆)-alkyl, or

(n) --CO₂ --(C₃ -C₆)cycloalkyl; or

R^(7a) and R^(7b) are independently:

(a) H,

(b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl,

(c) Cl, Br, I, F,

(d) CF₃, or

(e) when R^(7a) and R^(7b) are bonded to adjacent carbon atoms, they canbe joined to form a phenyl ring;

R^(8a) and R^(8b) are independently:

(a) H,

(b) aryl-(C₁ -C₄)-alkyl,

(c) heteroaryl-(C₁ -C₄)-alkyl,

(d) (C₁ -C₆)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: --CON(R^(2a))₂, --heteroaryl,--S(O)_(n) -R²¹ , --tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂ NH-heteroaryl,--SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN, --NR^(2a)COOR²¹, --OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁-C₄)-alkylamino, (C₁ -C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a),--O--COR^(2a) aryl, ##STR12## (e) --CO--aryl, (f) (C₃ -C₇)-cycloalkyl,

(g) Cl, Br, I, F,

(h) --OH,

(i) --OR²¹,

(j) --SH,

(k) --S(O)_(n) --(C₁ -C₄)-alkyl,

(l) --COR^(2a),

(m) --CO₂ H,

(n) --SO₃ H,

(o) --NR^(2a) R²¹,

(p) --NR^(2a) COR²¹,

(q) --NR^(2a) COOR²¹,

(r) --SO₂ NR^(2a),

(s) --SO₂ NR² R^(2a),

(t) --NO₂,

(u) --NHSO₂ CF₃,

(v) --CONR^(2a) R²¹,

(w) --(C₁ -C₄)-polyfluoroalkyl,

(x) --COOR²,

(y) --SO₃ H,

(z) --N(R^(2a))SO₂ R²¹,

(aa) --NR^(2a) CONR^(2b) R²¹,

(bb) --OC(═O)NR²¹ R^(2a),

(cc) --aryl,

(dd) --NHSO₂ CF₃,

(ee) --SO₂ NH--heteroaryl,

(ff) --SO₂ NHCOR²¹,

(gg) --CONHSO₂ R²¹,

(hh) --PO(OR²)₂,

(ii) --tetrazol-5-yl,

(jj) --CONH(tetrazol-5-yl),

(kk) --SO₂ NHCN,

(ll) --heteroaryl, ##STR13## --X¹ --X² --X³ --X⁴ -- is: (a) --Y--CR¹¹--CR¹¹ --CR¹² --CZ--,

(b) --CR¹¹ --Y'CR¹² --CZ--,

(c) --CR¹¹ --CR¹² --Y--CZ--,

(d) --Y--CR¹¹ --CZ--CR¹² --,

(e) --CR¹¹ --Y--CZ--CR¹² --, or

(f) --CR¹¹ --CR¹² --CZ--Y--;

Y is: O or S;

R⁹ and R¹⁰ are each independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) (C₁ -C₆)-alkyl,

(e) (C₁ -C₆)-alkoxy,

(f) (C₃ -C₆)-cycloalkyl,

(g) (C₁ -C₆)-alkoxy,

(h) --NHSO₂ R^(2a),

(i) hydroxy-(C₁ -C₄)-alkyl,

(j) (C₁ -C₄)-alkyl-aryl,

(k) S(O)_(n) -(C₁ -C₄)-alkyl,

(n) NR^(2a) R^(2a),

(q) CF₃,

(r) --SO₂ NHR^(2a),

(s) furyl,

(t) aryl, wherein aryl is phenyl or naphthyl, unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, NO₂, CF₃,(C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--CO₂ H, or --CO₂ -(C₁ -C₄)-alkyl, or

(u) when R⁹ and R¹⁰ re bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

R¹¹ and R¹² are independently:

(a) H,

(b) Cl, Br, I, R,

(c) NH₂,

(d) NH[(C₁ -C₄)-alkyl],

(e) N[(C₁ -C₄)-alkyl]₂,

(f) SO₂ NHR^(2a),

(g) CF₃,

(h) (C₁ -C₇)-alkyl,

(i) (C₁ -C₄)-alkoxy, or

(j) (C₃ -C₇)-cycloalkyl;

Z is:

(a) --CO₂ R^(2a),

(b) --NHSO₂ CF₃,

(c) --SO₂ NHR¹⁴,

(d) --1H-tetrazol-5-yl,

(e) --SO₂ NHCOR¹⁴, or

(f) --NHSO₂ R¹⁴ ;

R¹⁴ is

(a) aryl,

(b) heteroaryl,

(c) (C₃ -C₇)-cycloalkyl, or

(d) (C₁ -C₄)alkyl, unsubstituted or substituted with a substituentselected from the group consisting of aryl as defined above, heteroarylas defined above, --OH, --SH, (C₁ -C₄)-alkyl, --(C₁ -C₄)-alkoxy, --S(C₁-C₄)-alkyl, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, CO₂ --(C₁ -C₄)-alkyl,--NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃ H, PO(OH)(O--(C₁ -C₄)-alkyl;

(e) (C₁ -C₇)-alkoxy,

(f) O(CH₂)_(n+1) O(CH₂)_(s) CH₃,

(g) (CH₂)_(n+1) O(CH₂)_(s) CH₃,

(h) CH(R^(2a))₂,

(i) (C₁ -C₆)-polyfluoroalkyl, or

(j) 'NH(C₁ -C₆)-alkyl;

R¹⁵ is:

(a) H,

(b) aryl, unsubstituted or substituted with 1 or 2 substituents selectedfrom the group consisting of: Cl, Br, I, F --O--(C₁ -C₄)-alkyl, (C₁-C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl, --OH,--NH₂, (C₃ -C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl;

(c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of aryl as defined above, (C₃ -C₇)-cycloalkyl,Cl, Br, I, F, --OH, --NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--NH--SO₂ R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or

(d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6membered ring which can contain one or two heteroatoms selected from thegroup consisting of N, O, S, and wherein the substituents are membersselected from the group consisting of: --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkyloxy --CF₃, Cl, Br, I, F, or NO₂ ;

R¹⁶ is

(a) (C₁ -C₁₀)-alkyl,

(b) substituted (C₁ -C₁₀)-alkyl in which one or more substituent(s) isselected form

(1) hydroxy,

(2) (C₁ -C₅)-alkoxy,

(3) (C₁ -C₅)-alkoxycarbonyl,

(4) phenyl,

(5) carboxy, or

(6) C(50 O)NH--(C₁ -C₅)-alkyl,

(c) aryl, or

(d) aryl substituted with V and W;

V and W are selected from:

(a) H,

(b) (C₁ -C₅)-alkoxy,

(c) (C₁ -C₅)alkyl,

(d) hydroxy,

(e) --CN,

(f) --NO₂,

(g) --NR² R^(2a),

(h) --CO₂ R^(2a),

(i) --CF₃,

(j) I, Br, Cl, F,

(k) hydroxy-C₁ -C₄)-alkyl--,

(l) --1H-tetrazol-5-yl, or

(m) --NH--SO₂ CF₃ ;

R¹⁷ and R¹⁸ are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl--,

(c) heteroaryl-(C₁ -C₄)-alkyl--,

(d) (C₁ -C₄)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: --OH, --NH₂, guanidino, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁-C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a), --O--COR^(2a), CF₃ ;

(e) (C₁ -C₄)-alkenyl,

(f) --CO-aryl,

(g) (C₃ -C₇)-cycloalkyl,

(h) Cl, Br, I, F,

(i) --OH,

(j) --O--(C₁ -C₄)-alkyl,

(k) --(C₁ -C₄)-polyfluoroalkyl,

(l) --SH,

(m) --S(O)_(n) --(C₁ -C₄)-alkyl,

(n) --CHO,

(o) --CO₂ R^(2a),

(p) --SO₃ H,

(q) --NH₂,

(r) --NH[(C₁ -C₄)-alkyl],

(s) --N[(C₁ -C₄)-alkyl]₂,

(t) --NHCO₂ --(C₁ -C₄)-alkyl,

(u) --SO₂ NR² R^(2a),

(v) --CH₂ OCOR^(2a),

(w) --NH--SO₂ --(C₁ -C₄)-alkyl,

(x) 5 or 6 membered saturated heterocycle containing one nitrogen atomand optionally containing one other heteroatom selected from N, O, or S,such as pyrrolidine, morpholine, or piperazine,

(y) aryl,

(z) heteroaryl, or

(aa) tetrazol-5-yl; and

R²¹ is:

(a) aryl, unsubstituted or substituted with a substituent selected fromCl, Br, F or I, or

(b) (C₁ -C₄)-alkyl which is unsubstituted or substituted with:

i) NH₂,

ii) NH[(C₁ -C₄)-alkyl],

iii) N[(C₁ -C₄)-alkyl]₂,

iv) CO₂ H,

v) CO₂ (C₁ -C₄)-alkyl,

vi) OH,

vii) SO₃ H, or

viii) SO₂ NH₂ ;

(c) heteroaryl, or

(d) (C₃ -C₇)-cycloalkyl;

or a pharmaceutically acceptable salts thereof.

A class within the embodiment is when the structural formula is:##STR14##

A subclass within the embodiment is when the structural formula is:##STR15## or a pharmaceutically acceptable salt thereof, wherein thesubstituents are as defined above.

A subclass within this class is when the structural formula is:##STR16## wherein R¹ is: ethyl, n-propyl, n-butyl or pentyl;

R^(2c) is: H, COCH₃, CO₂ Me CO₂ Et, CONHCH₃, CON[CH₃ ]₂, COphenyl,CO-4-pyridinyl, CO₂ -n-butyl, CO-cyclopropyl, SO₂ -isopropyl,CONH-n-propyl, or ##STR17## R^(8b) is: N(n-butyl)CO-phenyl,

N(pentyl)CO-phenyl,

N(benzyl))CO-phenyl,

N(benzyl)CO₂ isobutyl,

N(pentyl)CO-4-pyridyl,

N(pentyl)CO-(4-chlorophenyl),

N(n-butyl)CO-(4-fluorophenyl),

N(methyl)CO₂ -isobutyl,

isopropyl,

N(benzyl)CON(methyl)(ethyl), or ##STR18## R¹¹ is: H or R¹¹ and R¹² canjoined to form an phenyl ring; R¹² is: H, (C₁ -C₆)-alkyl, (C₁-C₆)-alkoxy, --CH₂ -aryl, O(CH₂)_(n+1) O(CH₂)_(s) CH₃, (CH₂)_(n+1)O(CH₂)_(s) (CH₃, or CH₂ N[CH₂ CH₂ ]₂ O;

Y is: O, or S; and

Z is:

(a) CO₂ R²,

(b) 1H-tetrazol-5-yl,

(c) CONHSO₂ R¹⁴,

(d) SO₂ NHR¹⁴,

(e) NHSO₂ R¹⁴,

(f) SO₂ HNHCOR¹⁴, or

(g) NHSO₂ CF₃.

Another subclass of within this class is when the structural formula is:##STR19## or a pharmaceutically acceptable salt thereof.

Another subclass of within this class is when the structural formula is:##STR20## or a pharmaceutically acceptable salt thereof.

Another class within this embodiment is when the structural formula is:##STR21## or a pharmaceutically acceptable salt thereof.

Another class within this embodiment is represented by structuralformula: ##STR22## wherein: R¹ is: ethyl, n-propyl, n-butyl;

R¹⁶ is:

benzyl,

2-carboxyphenyl,

2-chlorophenyl,

2-trifluoromethylphenyl,

2-methylphenyl, or

2,6 dichloromethyl;

--X¹ --X² --X³ --X⁴ -- is:

(a) --Y--CR¹¹ --CR¹² --CZ--,

(b) --CR¹¹ --Y--CR¹² --CZ--, or

(c) CR¹ 1 --CR¹² --Y--CZ--;

R¹¹ is: H or R¹¹ and R¹² can joined to form an phenyl ring;

R¹² is: H, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, --CH₂ -aryl, O(CH₂)_(n+1)O(CH₂)_(s) CH₃, (CH₂)_(n+1) O(CH₂)_(s) CH₃, or CH₂ N[CH₂ CH₂ ]₂ O;

Y is: O, or S; and

Z is:

(a) CO₂ R²,

(b) 1H-tetrazol-5-yl,

(c) CONHSO₂ R¹⁴,

(d) SO₂ NHR¹⁴,

((e) NHSO₂ R¹⁴,

(f) SO₂ NHCOR¹⁴, or

(g) NHSO₂ CF₃.

Another class within this embodiment is when the structural formula is:##STR23## or a pharmaceutically acceptable salt thereof.

Another class within the embodiment of the invention is the structuralformula is ##STR24## wherein: R¹ is: ethyl, n-propyl, n-butyl,

R¹⁷ and R¹⁸ are independently:

hydrogen,

methyl,

carboxyl,

benzyl,

2-chlorophenyl,

2-trifluoromethylphenyl, or

2-tolyl;

--X¹ --X² --X³ --X⁴ -- is:

(a) --Y--CR¹¹ --CR¹² --CZ--,

(b) --CR¹¹ --Y--CR¹² --CZ--, or

(c) CR¹¹ --CR¹² --Y--CZ--;

R¹¹ is: H or R¹¹ and R¹² can joined to form an phenyl ring;

R¹² is: H, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, --CH₂ -aryl, O(CH₂)_(n+1)O(CH₂)_(s) CH₃, (CH₂)_(n+1) O(CH₂)_(s) CH₃, or CH₂ N[CH₂ CH₂ ]₂ O;

Y is: O, or S; and

Z is:

(a) CO₂ R²,

(b) 1H-tetrazol-5-yl,

(c) CONHSO₂ R¹⁴,

(d) SO₂ NHR¹⁴,

(e) NHSO₂ R¹⁴,

(f) SO₂ NHCOR¹⁴, or

(g) NHSO₂ CF₃.

The alkyl substituents recited above denote straight and branched chainhydrocarbons of the length specified such as methyl, ethyl, isopropyl,isobutyl, neopentyl, isopentyl, etc.

The alkenyl and alkynyl substituents denote alkyl groups as describedabove which are modified so that each contains a carbon to carbon doublebond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.

Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each whichmay be substituted or unsubstituted with other hydrocarbon substituents,and include for example cyclopropyl, cyclopentyl, cyclohexyl and4-methylcyclohexyl.

The alkoxy substituent represents an alkyl group as described aboveattached through an oxygen bridge.

The aryl substituent recited above represents phenyl or naphthyl.

The heteroaryl substituent recited above represents any 5- or 6-memberedaromatic ring containing from one to three heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur, for example, pyridyl,thienyl, furyl, imidazolyl, and thiazolyl.

GENERAL METHODS FOR PREPARATION OF COMPOUNDS OF GENERAL FORMULA I

The methods described in PART I and PART II below illustrate thepreparation of angiotensin II antagonists of Formula I. There areseveral general approaches to the synthesis of antagonists of Formula I,and it is taken as a general principle that one or another method may bemore readily applicable for the preparation of a given antagonist; someof the approaches illustrated below may not be readily applicable forthe preparation of certain antagonists of Formula I.

It should be recognized that antagonists of Formula I consist of aheterocyclic component designated above by formulas Ia through Ic and asubstituted benzyl substitutent which is attached to the heterocycliccomponent at a nitrogen atom. Thus, two generally applicable approachesto antagonists of formula I are these:

1. A heterocycle, designated above with Formulas Ia through Ic isprepared as described in PART I below. Then the heterocycle is alkylatedat a nitrogen atom with a substituted benzyl halide or pseudohalidegiving an alkylated heterocycle in the Schemes below, this alkylatingagent is often designated as "Ar--CH₂ Q where Q is a halide (--Cl,Br,I)or pseudohalide (--OMs, OTs, OTf). In some cases, alkylation may takeplace at more than one nitrogen atom of the heterocycle, and in thesecases, separation by fractional crystallization or by chromatographicmethods may be necessary for isolation of the desired product. In somecases, the alkylation step produces a fully-assembled antagonist ofFormula I, except that functional groups in the alkylating agent or inthe heterocycle may be present in protected form and requiredeprotection steps to be carried out to complete the synthesis. In othercases, the alkylation is carried out with a substituted benzylic halideor pseudohalide ("Ar--CH₂ Q"), but here the alkylation step is followedby subsequent steps which are required to assemble the substitutedbenzyl element of the antagonist of Formula I. The alkylation steps andsubsequent steps used to prepare antagonists of Formula I, are describedin PART II below.

Abbreviations used in the schemes and examples are listed in Table 1.

                  TABLE 1                                                         ______________________________________                                        Solvents:                                                                     DMF             dimethylformamide                                             HOAc (AcOH)     acetic acid                                                   EtOAc (EtAc)    ethyl acetate                                                 Hex             hexane                                                        THF             tetrahydrofuran                                               DMSO            dimethylsulfoxide                                             MeOH            methanol                                                      iPrOH           isopropanol                                                   Reagents                                                                      NBS             N-bromosuccinimide                                            AIBN            Azo(bis) isobutyronitrile                                     DDQ             Dichlorodicyanoquinone                                        Ac.sub.2 O      acetic anhydride                                              TEA             triethylamine                                                 DMAP            4-dimethylaminopyridine                                       PPh.sub.3       triphenylphosphine                                            TFA             trifluroacetic acid                                           TMS-Cl          trimethylsilyl chloride                                       Im              imidazole                                                     AcSK            potassium thioacetate                                         p-TsOH          p-toluenesulfonic acid                                        FMOC-Cl         9-Fluorenylmethyloxycarbonyl                                                  chloride                                                      Others:                                                                       rt              room temperature                                              TBDMS           t-butyldimethylsilyl                                          OTf             OSO.sub.2 CF.sub.3                                            Ph              phenyl                                                        FAB-MS (FSBMS)  Fast atom bombardment mass                                    spectroscopy                                                                  NOE             Nuclear Overhauser Effect                                     SiO.sub.2       silica gel                                                    trityl          triphenylmethyl                                               Bn              benzyl                                                        ______________________________________                                    

PART I: Preparation of the heterocycles shown in Formulas Ia, Ib, and IcA. Preparation of quinazolinones (Formula Ia) ##STR25##

Scheme I-1 illustrates the preparation of 1,2-disubstitutedquinazolin-4(1H)-ones of Formula Ia wherein J¹ =--C(O)-- and E is asingle bond. An appropriately substituted anthranilonitrile is acylatedusing the requisite acyl chloride. The resulting amide is alkylated withsodium hydride and the appropriate alkyl halide (or pseudohalide). Theresulting tertiary amide is then rearranged/cyclized with basic hydrogenperoxide¹. ##STR26## Q=Br, I, OTs, OTf Ar=is as defined as in thegeneric structure Formula I

2-Substituted quinazolinones may be prepared from substitutedanthranilonitriles as described in the literature and illustrated inScheme I-2. The appropriately substituted anthranilonitrile is acylatedusing the requisite acyl chloride then cyclized using basic hydrogenperoxide.¹ ##STR27##

Scheme I-3 shows an alternate preparation of 2-substitutedquinazolinones starting with the corresponding anthranilic acid. Theappropriately substituted anthranilic acid is treated with twoequivalents of the requisite acyl chloride in DMF with triethylamine andDMAP at 0° C. This is then heated to 110° C. for two hours after whichtime excess ammonium carbonate is added.² ##STR28##

Scheme I-4 illustrates the general preparation of 2,3-disubstitutedquinazolin-4-(3H)-ones of Formula Ia, wherein E is a single bond and K¹is --C(O)--. An appropriately substituted 2-substituted quinazolinone(see Scheme I-2 or Scheme I-3) is alkylated using sodium hydride and theappropriate alkyl halide (or pseudohalide). This reaction sometimesgives some O-alkylated product, generally less than 20% of the isolatedreaction products. ##STR29##

Schemes I-5, I-6, and I-7 provide an alternate route to compounds ofFormula Ia, wherein E is a single bond and K¹ is --C(O)--.

Two methods for preparing 3,1,4-benzoxazones are illustrated in SchemeI-5. Substituted anthranilic acids may be acylated and cyclized byheating them in DMF with an acyl chloride, triethylamine and DMAP.³Alternatively, they may also be prepared by heating an appropriatelysubstituted anthranil with an acyl chloride in pyridine.⁴

The necessary alkyl amine may then be prepared from the alkyl halide (orpseudohalide) using the standard literature procedures (Scheme I-6).⁵Then, the amine and the 3,1,4-benzoxazone are heated together to givethe desired 2,3-disubstituted quinazolinone 2 (Scheme I-7). ##STR30##

Substituted 2-alkylthioquinazolin-4(3H)-ones wherein K¹ is --C(O)-- andE is --S-- may be prepared from their corresponding substitutedanthranilic acids as shown in Scheme I-8. The amine from Scheme I-6 canbe converted to its isothiocyanate upon treatment with thiophosgene.This may then be reacted with an appropriately substituted anthranilicacid to give the desired 3-alkyl-2-mercapto-quinazolin-4(3H)-one.⁶ Asecond alkylation of the mercapto group then gives the desired2-alkylthio-3-alkylquinazolin-4(3H)-one.⁷ ##STR31##

Similarly, 2-alkoxyquinazolin-4(3H)-ones wherein K¹ is --C(O)-- and B is--O-- may be prepared from their corresponding substituted anthranilicacids as shown in Scheme 9.⁸ Alkylation with the appropriate alkylhalide according to the methods developed by Lange and Sheibley⁹ thengives the final product 17. ##STR32##

Scheme I-10 illustrates a possible route to the isomeric1,2-disubstituted quinazolin-4(1H)-ones wherein J¹ is --C(O)-- andwherein E is --S-- or --O--. An anthranilonitrile can be acylated withan alkyl haloformate or an alkylthiol haloformate.¹⁰ This may then bedeprotonated and alkylated with the appropriate alkyl halide to give theintermediate carbamate nitrile shown.¹¹ Conversion of the intermediatethen could occur when the material is treated with basic hydrogenperoxide to yield the desired product 20. ##STR33##

Scheme I-11 illustrates the method by which a2-amino-3-alkylquinazolinone can be made. The 2-mercaptoquinazolinone(14) shown in Scheme I-8 can be treated with sulfuryl chloride to givethe corresponding 2-chloroquinazolinone.¹² Displacement of the chloridewith an R¹ amine then gives 20 with B=NH.¹³ ##STR34##

Scheme I-12 illustrates the method by which a2-amino-1-alkylquinazolinone can be made. The products from Scheme I-10can be used as a synthetic intermediate if the initial R¹ is aprotecting group such as benzyl or t-butyl.¹⁴ Deprotection andsubjection of the resulting 2-mercapto-1-alkyl-quinazolinone to the sameconditions used in Scheme I-11 will result in the formation of thedesired 2-amino-1-alkylquinazolin-4(1H)-one. Alternatively, the sulfidemay be displaced directly by an R¹ amine as shown in Scheme I-13 (R¹--S-- and R¹ --NH₂ may or may not have the same R¹). ##STR35##

The preparation of quinazolinones of general Formula Ia bearingsubstituted C-6 amino groups may be accomplished as illustrated inSchemes I-14 through I-16. In order to prepare these derivatives, theamide group of a 6-nitroquinazolin-4(3H)-one is usually first protectedwith an acid labile protecting group as shown in Scheme I-14. Forinstance, reaction of the generalized 6-nitroquinazolin-4(3H)-one (24)with a base such as sodium hydride in DMF followed by addition ofbis(4-methoxyphenyl)methyl chloride affords the N-protected derivative25. The nitro group of 25 may be reduced to the amine 26 by reductionwith hydrogen over palladium on carbon. The amine (26) may then bereacted with a variety of reagents known to form derivatives of aminessuch as alkyl- or aryl-carboxylic acid chlorides, chloroformates,sulfonyl and sulfamoyl chlorides, isocyanates and isothiocyanates.Scheme I-14 illustrates the derivatization of amine 26 with ageneralized chloroformate to afford substituted carbamates such as 27.The acylation of amine 26 with a chloroformate is best carried out inthe presence of a strong base such as sodium hydride to deprotonate theamine. This anion then reacts readily with chloroformates to give thesubstituted carbamates 27. The carbamate (27) may be isolated, thendeprotonated with lithium bis(trimethylsilyl)amide and alkylated to givethe N,O-disubstituted carbamates 28. Alternatively, this process may becarried out in one flask by first deprotonating the aniline (i.e. withsodium hydride in DMF), reacting the anion with an acyl halide orchloroformate, then treating the intermediate with an equivalent of astrong base such as lithium bis(trimethylsilyl)amide and finally addingan alkylating agent to obtain 28. The carbamoyl-substitutedquinazolinones 27 and 28 may be cleanly deprotected under acidicconditions such as trifluoroacetic acid-anisole to afford theheterocycles 29 and 30 respectively. ##STR36##

Scheme I-15 illustrates the reaction of amine 25 with isocyanates togive disubstituted ureas (31). Tetrasubstituted and trisubstituted ureassuch as 34 and 35 may be prepared from the benzyl carbamate 27 as shownin Scheme I-16. Thus, treatment of 27 with the magnesium salt of asecondary amine formed from the secondary amine and methylmagnesiumbromide affords the trisubstituted urea 32. Trisubstituted ureas (32)may be N-alkylated by deprotonation of the remaining hydrogen withlithium bis(trimethylsilyl)amide followed by alkylation with an alkyliodide to give 33. The urea-substituted quinzolines 32 and 33 may becleanly deprotected under acidic conditions such as trifluoroaceticacid-anisole to afford the heterocycles 34 and 35 respectively. Theamine 26 (Scheme I-14) may be derivatized or converted to otherfunctional groups using chemical procedures well known to those skilledin the art. After the appropriate 6-substituent has been constructed theprotecting group may be removed by treatment with trifluoroacetic acidin the presence of anisole as illustrated in Schemes I-14 through I-16.The heterocycles obtained in this manner may be incorporated intoAngiotensin II Antagonists of general Formula Ia as described in PartII. ##STR37##

For a general review of the synthesis and reactivity of2,3-disubstituted pyrido[2,3-d] or [3,4-d] or [3,2-d] or[4,3-d]pyrimidin-4(3HO-ones, see A. R. Katritzky, et al., ComprehensiveHeteocyclic Chemistry, vol. 3, 201 (1984) and W. J. Irwin, et al.,Advances in Heterocyclic Chemistry, vol. 10, 149 (1969).

QUINAZOLINONE REFERENCES

¹ E. C. Taylor, R. J. Knopf, A. L. Borror, J. Am. Chem. Soc. (1960) 82,3152.

R. L. McKee, M. K. McKee, R. W. Bost, J. Am. Chem. Soc. (1964), 68,1902.

A. Khan, R. K. Saksena, Pharmazie (1988) 43 H, 12.

² M. T. Bogert, W. F. Hand, J. Am. Chem. Soc. (1906) 28, 94.

³ See A. Khan, reference 1.

L. A. Errede, J. J. McBrady, H. T. Oien, J. Org. Chem. (1977) 42, 656.

L. A. Errede, J. Org. Chem. (1976) 41 1763.

L. A. Errede, H. T. Oien, D. R. Yarian, J. Org. Chem. (1977) 42, 12.

⁴ K. Wunsch, A. J. Boulton, Adv. Het. Chem. (1967) 8, pp 326-9, andreferences therein.

I. R. Gambhir, S. S. Joshi, J. Ind. Chem. Soc. (1964) 41, 47.

⁵ Bayley, Stranding, Knowles, Tetrahedron. Lett. (1978) 3633.

Rolla, J. Org. Chem. (1982) 47, 4327.

Gibson, Bradshaw, Angew. Chem. Int. Ed. Engl. (1968) 7, 919.

⁶ R. G. Dave, G. S. Mewada, G. C. Amin, J. Ind. Chem. Soc. (1960) 37,595.

⁷ J. E. McCarty, E. L. Haines, C. A. VanderWerf, J. Am. Chem. Soc.(1960) 82, 964.

P. N. Bhargava, P. Ram, Bull. Chem. Soc. Jap. (1965) 38, 342.

M. R. Chaurasia, A. K. Sharma, Heterocycles (1983) 20, 1549.

K. Lempert, G. Doleschall, Chem. Ber. (1963) 96, 1271.

H. Singh, K. S. Narang, J. Ind. Chem. Soc. (1963) 40, 545.

M. S. Dhatt, K. S. Narang, J. Ind. Chem. Soc. (1954) 31, 787.

M. S. Dhatt, K. S. Narang, J. Ind. Chem. Soc. (1954) 31, 864.

D. S. Bariana, H. S. Sachdev, K. S. Narang, J. Ind. Chem. Soc. (1955)32, 647.

⁸ Griess, Ber. Deut. Chem. Ges. (1869) 2, 415.

⁹ N. A. Lang, F. E. Sheibley, J. Am. Chem. Soc. (1933) 55, 1188.

¹⁰ H. B. Milne, S. L. Razniak, R. P. Bayer, D. W. Fish, J. Am. Chem.Soc. (1960) 82, 4582.

E. J. Corey, M. G. Bock, A. P. Kozkowski, A. V. R. Rao, D. Floyd, B.Lipschutz, Tetrahedron Lett. (1978) 1051.

M. Bergmann, L. Zervas, Ber. (1932) 65 1192.

¹¹ R. L. Dannley, M. Lukin, J. Org. Chem. (1957) 22, 268.

R. Zibuck, N. J. Liverton, A. B. Smith, J. Am. Chem. Soc. (1986) 10,82451.

¹² D. J. Brown, Fused Pyrimidines, Part I Quinazolines, (1967), J. Wiley& Sons, p. 222.

¹³ D. J. Brown, Fused Pyrimidines, Part I Quinazolines, (1967), J. Wiley& Sons, p. 323.

¹⁴ T. W. Greene, Protective Groups in Organic Synthesis, (1981), J.Wiley & Sons, pp. 193-217.

B. Preparation of triazolinones, triazolinethiones and triazolinimines(Formula Ib) ##STR38##

The compounds of Formula Ib can be prepared by a variety of methodstypified by those described below in Schemes I-17 to I-28. Generalsynthetic methods for 2,4,5-trisubstituted-1,2,4-triazolin-3(4H)-onesand -triazolin-3(4H)-thiones are discussed in books or review articlessuch as:

(1) C. Temple and J. A. Montgomery, "Triazoles: 1,2,4" (Vol. 37 of TheChemistry of Heterocyclic Compounds, A. Weissberger and E. C. Taylor,eds.), Wiley-Interscience, New York, 1981, pp. 365-442.

(2) J. B. Polya, Comprehensive Heterocyclic Chemistry, The Structure,Reactions, Synthesis and Uses of Heterocyclic Compounds, A. R. Katritzkyand C. W. Rees, eds., Vol. 5, Pergamon Press, Oxford, 1984, pp. 733-790.

(3) J. H. Boyer, Heterocyclic Compounds, R. C. Elderfield, ed., Vol. 7,John Wiley & Sons, New York, 1961 pp. 384-461.

In general, the compounds of Formula Ib are constructed in such a waythat N¹ and N² of the triazole ring are derived from hydrazine or ahydrazine derivative, while N⁴ of the triazole and the 4-(arylmethyl)substituent are derived directly or indirectly from a suitablysubstituted benzylamine (or isocyanate or isothiocyanate) or from abenzyl halide (or methanesulfonate, p-toluenesulfonate, etc.).

Although the Reaction Schemes described below are reasonably general, itwill be understood by those skilled in the art of organic synthesis thatone or more functional groups present in a given compound of Formula Ibmay render the molecule incompatible with a particular syntheticsequence. In such a case an alternative route, an altered order ofsteps, or a strategy of protection and deprotection may be employed. Inall cases the particular reaction conditions (including reagents,solvent, temperature, and time) should be chosen so that they areconsistent with the nature of the functionality present in the molecule.

The Reaction Schemes below have been generalized for simplicity. It isto be understood that the "ArCH₂ " substituent present at N⁴ of thetriazole derivatives or in their precursors is any substitutedarylmethyl moiety consistent with the definition of the N⁴ substituentin Formula I or which may be transformed to such a grouping eitherbefore or after the assembly of the triazole ring system. Suchtransformations may involve protection and/or deprotection steps, asdescribed above in the "General Methods" section or other modifications.It is also to be understood that in most of the Reaction Schemes, the"ArCH₂ " (Ar=aryl) substituent is consistent with the definition ofFormula I.

It is further to be understood that in the generalized schemes below,unless specified otherwise, the R¹ and R¹⁶ groups representfunctionalized or unfunctionalized alkyl, aryl, heteroaryl, aralkyl, andthe like. The moiety, R¹⁶ Q, represents an alkylating agent in which R¹⁶is typically a functionalized or unfunctionalized alkyl or aralkylgroup, while Q is a leaving group such as chloro, bromo, iodo,methanesulfonate, or p-toluenesulfonate. In structures showing an "X"group double-bonded to a carbon atom (as in 22 and products derivedtherefrom), M is O or S. ##STR39##

One of the most widely used routes to2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-ones(2,4,5-trisubstituted-1,2,4-triazolin-3(4H)-ones) is shown in ReactionScheme I-17 in its adaptation for the synthesis of compounds of FormulaIb. Reaction of a carboxylic acid hydrazide 1 (readily obtained from thecorresponding ester) with the appropriate arylmethyl isocyanate 2 givesthe 1-acyl-4-(arylmethyl)semicarbazide 3. The isocyanate 2 itself isobtainable by well-known methods from various sources, including the(arylmethyl)amine (by phosgene treatment), the arylmethyl halide (bytreatment with cyanate anion), and the arylacetic acid or derivative(via Curtius rearrangement of the acyl azide). Upon heating in thepresence of hydroxide or alkoxide, cyclization of 3 to the triazolinone4 occurs. Finally, in the presence of a base (e.g., sodium hydride,sodium ethoxide, sodium hydroxide, or potassium carbonate), 4 isconverted to the trisubstituted triazolinone 5 on treatment with asuitable alkylating agent R¹⁶ Q, where R¹⁶ is alkyl, aralkyl, etc., andQ is bromo, iodo, chloro, methanesulfonate, p-toluenesulfonate, and thelike. Such reaction pathways have been described by D. L. Temple, Jr.,and W. G. Lobeck, Jr., U.S. Pat. No. 4,487,773 (1984), R. E. Gammans, D.W. Smith, and J. P. Yevich, U.S. Pat. No. 4,613,600 (1986), and (inpart) H. Gehlen and W. Schade, Liebegs Ann. Chem. 675, 180 (1964), G.Palazoo, U.S. Pat. No. 3,857,845 (1974), and K. H. Hauptmann and K.Zeile, British Patent 971,606 (1964). A modified approach to anintermediate of type 3 and its subsequent cyclization to a triazolinoneanalogous to 4 have been reported by H. Hrebabecky and J. Barenek,Collect. Czech. Chem. Commun., 50, 779 (1985). ##STR40##

A highly useful alternative route to 4 is shown in Reaction Scheme I-18.This approach has been described by M. Pesson, S. Dupin, and M. Antoine,Compt. Rend., 253, 285 (1961) and R. Un and A. Ikizler, Chim. Acta.Turc., 3, 113 (1975). Addition of ethyl carbazate (8) to the imidate 7(which is readily prepared from the corresponding nitrile 6) yields anadduct 9, which can be converted to the triazolinone 4 on heating withthe (arylmethyl)amine 10 (typically at temperatures from 70°-150° C.) Asin Reaction Scheme I-17, 4 can be alkylated to give the trisubstitutedtriazolinone 5. ##STR41##

The procedures of Reaction Schemes I-17 and I-18 are not suitable forthe introduction of most aryl or heteroaryl substituents at N². Incontrast, the procedures of Reaction Schemes I-19 to I-22 are especiallywell suited for the synthesis of compounds of Formula Ib having aryl orheteroaryl substituents at N², since the triazolinone ring isconstructed with the N² -substituent in place, whereas the N⁴-substituent is introduced subsequently by alkylation. Reaction SchemeI-19 presents a route patterned after that reported by K. Yabutani, K.Taninaka, M. Kajioka, K. Takagi, H. Matsui, K. Sutoh, and M. Yamamota,European Patent Application 220, 952 (1987). The N-carbethoxy imidate 11(obtained by reaction of 7 with ethyl chloroformate) is treated with anarylhydrazine 12 (or analog), typically at about 40°-50° C.) in thepresence of a tertiary amine such as triethylamine which effectscyclization to the triazolinone 13. In the presence of a suitable base(e.g., sodium hydride, sodium alkoxide, sodium hydroxide) treatment of13 with the appropriate ArCH₂ Q, where Q=bromo, iodo, chloro,methane-sulfonate, p-toluenesulfonate, and the like, yields the N⁴-alkylated product 15. A variant of the method using a thioimidate hasbeen described by M. Kajioka, H. Kurono, K. Okawa, and M. Harada, U.S.Pat. No. 4,318,731 (1982). ##STR42##

An alternative route to the N² -substituted triazolinone intermediate 13is shown in Reaction Scheme I-20. This chemistry has been described byT. N. Gosh and M. V. Betrabet, J. Indian Chem. Soc., 7, 899 (1930), S.Bellioni, Ann. Chim. (Rome), 52, 187(1962), G. Palazzo and G. Picconi,Boll. Chim. Farm., 105, 217 (1966), and British Patent 1,021,070 (1966).An acid chloride 16 is heated with urethane (17) (typically at 80°-100°C.), to give the acylurethane 18. Reaction of 18 with an arylhydrazine12 and phosphorus pentoxide (usually in toluene or xylene at reflux)gives 13, which can then be further alkylated on N⁴ as in ReactionScheme I-19. A (thioacyl)urethane modification of this pathway has beenreported by D. L. Temple, Jr., and W. G. Lobeck, Jr., U.S. Pat. No.4,487,773 (1984). ##STR43##

A variation of Reaction Scheme I-20, shown in Reaction Scheme I-21, hasbeen described by P. Gold-Aubert, D. Melkonian, and L. Toribio, Helv.Chim. Acta, 47, 1188 (1964) and A. L. Langis, U.S. Pat. No. 3,499,000(1970). The readily prepared acylurea 19 upon heating with anarylhydrazine 12 (at about 150°-200° C.) is converted to thetriazolinone intermediate 13. R1 REACTION SCHEME I-22? ? ##STR44##

In a quite different approach (Reaction Scheme I-22), L. Maravetz, U.S.Pat. No. 4,705,557 (1987) and G. Theodoridis, International PatentApplication WO87/03782 (1987) disclose condensing an α-keto acid 20 withthe arylhydrazine 12 to give derivatives such as 21, which can beconverted to the triazolinone intermediate 13 by heating withdiphenylphosphoryl azide and triethylamine (typically at 75°-115° C.).In the last step, an intermediate acyl azide loses nitrogen andundergoes the Curtius rearrangement to an isocyanate, which undergoesring closure. As shown in Reaction Scheme I-19, 13 can then be alkylatedon N⁴ to give the trisubstituted triazolinone 15. ##STR45##

2,4,5-Trisubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones(2,4,5-trisubstituted-1,2,4-triazolin-3(4H)-thiones) cannot generally beprepared by routes analogous to those in Reaction Schemes I-17 to I-22because of the propensity for alkylation to occur on sulfur rather thanon the open ring nitrogen. It is thus preferable to have all of thesubstituents in place at the time of the ring closure to form theheterocycle. As shown in Reaction Scheme I-23, for certain R¹⁶ groups(e.g., R¹⁶ =CH₃), reaction of the hydrazine derivative 23 with theappropriate isocyanate or isothiocyanate 22 yields the 2,4-disubstitutedsemicarbazide or thiosemicarbazide 24. Acylation of 24 gives 25, whichcan be cyclized upon heating with hydroxide or alkoxide to give thetrisubstituted triazolinone or triazolinethione 26. This approach hasbeen detailed by J. M. Kane and F. P. Miller, U.S. Pat. No. 4,775,688(1988) and G. F. Duffin, J. D. Kendall, and H. R. J. Waddington, J.Chem. Soc., 3799 (1959). Alternative methods of ring closure, such asheating 24 with the orthoester 27, can also be utilized. ##STR46##

In Reaction Scheme I-24, acylation of an aryl- or heteroaryl hydrazinegives 28, which can be reacted with the isocyanate or isothiocyanate 22to yield the 1-acyl-2,4-disubstituted-semicarbazide or-thiosemicarbazide 29. Cyclization of 29 upon heating with hydroxide oralkoxide affords the triazolinone or triazolinethione 30. This chemistryhas been described by H. Gehlen and W. Schade. Liebigs Ann. Chem., 675,180 (1964). ##STR47##

The method of F. Russo, M. Santagati, and G. Pappalardo [Ann. Chim.(Rome), 62, 351 (1972] (Reaction Scheme I-45) is useful for thesynthesis of trisubstituted triazolinones and triazolinethiones havingbenzylic substituents at N². Treatment of a hydrazide 1 with an aromaticor heteroaromatic aldehyde followed by reduction with sodium borohydridegives the substituted hydrazide 31. Reaction of 31 with the isocyanateor isothiocyanate 22 affords the semicarbazide or thiosemicarbazidederivative 32, which is cyclized to the triazolinone or triazolinethione33 upon heating with hydroxide or alkoxide. ##STR48##

In another approach (Reaction Scheme I-26), imidate 7 is treated with asubstituted hydrazine 23 (especially an aryl or heteroaryl hydrazine) togive the amidrazone 34. Heating 34 with the isocyanate or isothiocyanate22 gives the triazolinone or triazolinethione 26. Syntheses of this typehave been reported by M. Santus, Acta Pol. Pharm. 37, 293 (1980); T.Bany, Rocz. Chem., 42. 247 (1968); and, T. Bany and M. Dobosz, Ann.Univ. Mariae Curie-Sklodowska, Sect., AA, 26/27, 23 (1971). ##STR49##

A route to 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-imines(2,4,5-trisubstituted-1,2,4-triazolin-3(4H)-imines) is outlined inReaction Scheme I-27. Reaction of the (arylmethyl)amine 10 with benzoylisothiocyanate (or by the other means) gives the substituted thiourea35, which is methylated to prepare the isothiourea derivative 36.Compound 36 can be transformed to the acrylaminoguanidine 37 by reactingwith the hydrazide 1 or to the aminoguanidine 38 by reacting withhydrazine. Ring closure of 37 by heating in DMF or cyclization of 38with carboxylic acid 39 at elevated temperature affords theaminotriazole 40, which can be separated from the isomer 41. Suchpathways have been described by G. J. Durant, G. M. Smith, R. G. W.Spickett, and S. H. B. Wright, J. Med. Chem., 9, 22 (1966) and E.Akerblom, Acta Chem. Scand., 19, 1135 (1965). Finally, alkylation of 40with the appropriate Ar--CH₂ --Q (where Q is a leaving group such asiodo, bromo, chloro, p-toluenesulfonate, or methanesulfonate) leads tothe triazolinimine 42, which can be separated from any other isomers orby-products formed during the reaction. This method has been describedby E. B. Akerblom and D. E. S. Campbell, J. Med. Chem., 16, 312 (1973).##STR50##

The route shown in Reaction Scheme I-28 utilizes chemistry reported byE. Akerblom, Acta Chem., Scand., 19, 1135 (1965). The substitutedisothiourea 43 is treated with amine 10 to give the aminoguanidinederivative 44. Acylation of 44 with the acid chloride 16 provides theintermediate 45, which can be cyclized by heating the hydroxide oralkoxide. The desired triazolinimine 46 is separated from the isomericproduct 47.

C. Preparation of Pyrimidinones (Formula Ic)

The compounds of Formula Ic wherein either J² or K² is --C(O)-- aresynthesized as illustrated in Schemes I-29 to I-41 below. ##STR51##

Pyrimidinones of formula Ic (wherein J² is --C(O)--) substituted in the1,2,5, and 6-positions may be synthesized as shown in Scheme I-29.Amidines with an R¹ substituent may be reacted with a β-carbonyl esterto give a 4-hydroxypyrimidine. Conversion of the hydroxy group to achloride then to an amine can be achieved by first treating the4-hydroxypyrimidine with POCl₃ then with ammonia.¹ Reaction of the4-aminopyrimidine with the appropriate alkyl halide followed bytreatment with aqueous hydroxide gives the substitutedpyrimidin-4(1H)-one. ##STR52## Q is a leaving group (--Cl, --Br, --I,--OTs, etc).

Scheme I-30 provides the method by which the isomer (wherein K² is--C(O)--) 2,3,5, and 6-substituted pyrimidinones may be synthesized. Aβ-carbonyl ester is converted into its corresponding β-aminocrotonatewith ammonia.³ This is then acrylated with an R¹ -containing acylchloride (R¹ COCl) and cyclized to a 3.1-oxazin-4-one. When the3,1-oxazin-4-one is reacted with the substituted benzylamine, thedesired fully substituted pyrimidione 4 results.⁴ ##STR53##

Alternatively, Scheme I-31 shows how an R⁶ imidate may be converted toan amidine with the substituted benzylamine, followed by treatment withan appropriately substituted β-carbonyl ester to give the desiredpyrimidinone 4.⁵ ##STR54##

A third alternative is illustrated in Scheme I-52. A simple amidine canbe reacted with an appropriately substituted β-carbonyl ester to givethe 3-unsubstituted pyrimidinone. This can then be alkylated at the3-position with KOH is methanol (or with NaH in DMF) and theappropriately substituted alkyl halide to give 4. ##STR55##

Scheme I-33 illustrates the general synthesis of pyrimidinones ofFormula Ic in which B is a sulfur atom. Thiourea when condensed with aβ-carbonyl ester gives the 2-thiouracil. This can bebis-trimethylsilylated using hexamethyldisilazane, then alkylatedsequentially on the 1-nitrogen atom and then on the sulfur atom usingchemistry developed by H. Vorbruggen and P. Strehlke.⁶ By this method,one can then obtained compounds of Formula Ic wherein J² is --C(O)-- andB is a sulfur atom. ##STR56##

The isomeric 2,3-dialkylated thiouracils may be synthesized as shown inScheme I-34. Thiourea can be condensed with an appropriately substitutedβ-carbonyl ester to give the 5,6-disubstituted-2-thiouracil.⁷ This maythen be alkylated sequentially at the sulfur with an R¹ halide, and thenat the nitrogen atom with an appropriately substituted alkyl halide togive the desired tetrasubstituted pyrimidinone 4. ##STR57##

Alternatively, as illustrated in Scheme I-35, an isothiocyanate can beconverted into a thiourea by the addition of ammonia.⁸ This can then becondensed with the appropriately substituted β-carbonyl ester to givethe 3,5,6-trisubstituted-2-thiouracil.⁹ Alkylation at the sulfur atomwith base and an R¹ halide then gives the desired pyrimidinone 4.##STR58##

Scheme I-36 provides a method by which the 2-alkoxy-1-alkylpyrimidinonesmay be synthesized. An appropriately substituted β-keto amide¹⁰ iscyclized with carbonyl diimidazole¹¹ and converted to the correspondinguracil upon treatment with the appropriately substituted primaryamine.¹² The uracil can then be converted to the2-alkoxy-1-alkylpyrimidinone by treatment with an R¹ orthoester.¹³Alternatively, Scheme I-37 shows how the methods of Wittenburg¹⁴ mightbe employed to accomplish the same transformation. ##STR59##

Scheme I-38 shows how the isomeric 2-alkoxy-3-alkylpyrimidinones can beprepared. The primary amine can be converted into an isocyanate¹⁵, thenconverted to the corresponding urea by treatment with ammonia. Reactionof the urea with an appropriately substituted β-keto ester then givesthe 3-substituted uracil.¹⁶ Conversion of the uracil to thecorresponding 2-alkoxy pyrimidinone is achieved using an R¹orthoester.¹⁷ Alternatively, a β-aminocrotonate can be reacted with theisocyanate, as shown in Scheme I-39¹⁸, then alkoxylated with an R¹orthoester.

The β-keto esters used in the preceding schemes can be synthesizedreadily from ethyl hydrogen malonate and an R¹⁷ acid chloride as shownin Scheme I-40.¹⁹ R¹⁷ may be alkyl or aryl. Alkylation of this materialwith an alkyl halide (R¹⁸ -Q) is achieved using sodium hydride in DMSOor by other classical methods. R¹⁸ may be alkyl or aralkyl suitableprotected, if necessary, so as not to react with NaH. Scheme I-41illustrates the preparation of the 5-alkoxycarbonyl moiety and thecorresponding 5-amino derivatives. ##STR60##

1. K. Wunsch, A. J. Boulton, Adv. Het. Chem., (1967), 8, 326-9 andreferences therein.

2. D. J. Brown, E. Hoerger. S. F. Mason, J. Chem. Soc., (1955) 4035.

3. V. Prelog, et al, Ber. (1945) 28 1684.

4. H. B. Kagan, M. Y. H. Suen, Bull. Soc. Chim. Fr. (1966) 1819.

W. Steglich, E. Buschmann, O. Hollitzer, Angew, Chem. Int. Ed. Engl.(1974) 13 533.

F. Eiden, B. S. Nagar, Naturwissenschaften (1963) 50 43.

A. Krantz, B. Hoppe, J. Am. Chem. Soc., (1975) 97 6590.

5. A. Sitte, H. Paul, Chem. Ber. (1969(102 615.

6. H. Vorbruggen, P. Strehlke, Chem. Ber. (1973) 106 3039.

7. D. J. Brown, The Pyrimidines, (1962), J. Wiley & Sons, p. 300.

8. D. J. Brown, The Pyrimidines, (1962), J. Wiley & Sons, P. 437.

9. R. G. Dave, G. S. Mewada, G. C. Amin, J. Ind. Chem. Soc. (1960) 37595.

M. Sano, Chem. Pharm. Bull. (1962) 10 313.

C. Piantadosi, V. G. Skulason, J. L. Irvin, J. M. Powell, L. Hall, J.Med. Chem. (1964) 7 337.

10. M. K. Jain, Ind. J. Chem. (1963) 1 274. P. C. Kuzma, L. E. Brown, T.M. Harris, J. Org. Chem. (1984) 49 2015.

11. S. De Bernardo, M. Weigele, J. Org. Chem. (1977) 42 109.

12. T. Kinoshita, H. Tanaka, S. Furukawa, Chem. Pharm. Bull. (1986) 341809.

13. F. Yoneda, T. Nagamatsu, M. Takamotor, Chem. Pharm. Bull. (1983) 31344.

14. Wittenburg, Angew, Chem. (1965) 77 1043.

15. S. Osaki, Chem. Rev. (1972) 72 457.

16. Gabriel, Colman, Ber. (1904) 37 3657.

17. F. Yoneda, T. Nagamatsu, M. Takamoto, Chem, Pharm. Bull. (1983) 31344.

18. R. Behrend, F. C. Meyer, Y. Buckholz, Liebigs Ann. Chem. (1901) 314200.

19. W. Wierenga, H. I. Skulnick, Org. Syn, (91983) 61, 5.

PART II: Preparation of substituted methylphenylthiophenes and furanderivatives and alkylation with the heterocycles described in Part I.

The desired bromomethylphenyl thiophene necessary for the constructionof 3,4-disubstituted thiophenes of formula I, where X¹ --X² --X³ --X⁴=--CH--S--CH--CZ-- and Z=tetrazolyl are prepared as illustrated inscheme II-1. Palladium (0) catalyzed coupling of p-tolyltrimethyltinwith 3,4-dibromothiophene in refluxing toluene or DMF at 70°-80° C. for12 to 24 hours provides 3-bromo-4-tolylthiophene. This bromide could bedisplaced with cyanide using copper (I) cyanide in hot quinoline. Thenitrile is converted to the trityl protected tetrazole in a three stepprocedure using trimethyltin azide in refluxing toluene followed bytreatment with acid and finally protection with triphenylmethyl chloridein the presence of triethyl amine using CH₂ Cl₂ or CHCl₃ as solvent. Theprotected tetrazole compound can be treated with N-bromosuccinimideinrefluxing carbontetrachloride in the presence of a catalytic amount ofAIBN or benzoylperoxide to provide the necessary bromoethylphenylthiophenes. Substitution in the 2-position of the thiophene ring can beaccomplished by reaction with nBuLi or tBuLi followed by quenching withan appropriate electrophile. Again reaction with N-bromosuccinamide, asbefore, provides the required bromomethylphenyl thiophenes. ##STR61##

The desired bromomethylphenyl thiophene necessary for the constructionof 3,4-disubstituted thiophenes of Formula I, where X¹ --X² --X³ --X⁴=--CH--S--CH--CZ-- and Z=SO₂ NHCOR⁷, are prepared as illustrated inscheme II-2. Sequential dianion formation of 2a with nBulI or tBuLi inTHF at -20° C., followed by quenching with TMSCl provides 2. Treatmentwith strong base such as nBuLi, LDA or tBuLi, followed by quenching withBr₂ affords the bromo thiophene derivative 2c. Palladium catalyzedcross-coupling of 2c with p-tolyltrimethyltin using PdCl₂ (PPh₃)₂ in hotDMF or Pd(PPh₃)₃ in hot toluene provides 2d. Biaryl compound 2d can betreated with N-bromosuccinimide in refluxing carbontetrachloride orbenzene in the presence of a catalytic amount of AIBN or benzoylperoxideto provide the necessary bromomethylphenyl thiophenes. ##STR62##

The desired methanesulfonylmethylphenyl thiophenes and furans necessaryfor the construction of 2,3-disubstituted thiophenes and furans (Y=O orS) of formula I, where X¹ --X² --X³ --X⁴ =--CH--CH--S--CZ-- andZ=tetrazolyl, are prepared as illustrated in scheme II-3.2-Cyanothiophene and 2-cyanofuran are converted to their respectiveprotected tetrazoles by reaction with trimethyltin azide in refluxingtoluene followed by treatment with dilute mineral acid and finallyprotection with triphenylmethyl chloride in the presence of triethylamine in a chlorinated solvent. Reaction of the heterocycle with astrong base such as nBuLi followed by quenching with trimethylsilylchloride fixes a trimethyl silyl group in the 5-position. Again reactionwith a strong base (tBuLi, nBuLi or LDA), this time, followed byquenching with trimethyltin chloride provides the protectedtetrazolylaryltrimethyltin derivative. Palladium catalyzed crosscoupling with methyl p-iodobenzoate in refluxing toluene or hot MDF forseveral hours is followed by lithium aluminum hydride reduction andconversion of the subsequent alcohol to the mesylate withmethanesfulonyl chloride and treithyl amine. ##STR63##

The desired bromomethylphenyl thiophenes and furans necessary for theconstruction of 2,3-disubstituted thiophenes and furans (Y=O or S) offormula I, where X¹ --Z² --X³ --X⁴ =--CR¹² --S--CZ-- and Z=SO₂ NHCOR⁷and R¹¹ =R¹² =H, are prepared as illustrated in scheme II-4.Palladium(O) catalyzed coupling of p-tolyltrimethyltin with a3-bromothiophene or furan derivative in refluxing toluene provides the3-tolylthiophene or 3-bromothiophene or furan. If the 5-position of thefuran or thiophene is unsubstituted it is protected as was carried outin scheme II-3 with a trimethylsilyl group. Reaction with a strong basesuch as nBuLi, generating the anion at the 2-position, is followed bysuccessive quenching with SO₂ (g) followed by N-chlorosuccinamide. Theresultant sulfonyl chloride is reacted with tbutyl amine in CH₂ Cl₂ andis followed by benzylic bromination with N-bromosuccinimide utilizingAIBN or benzoylperoxide as a radical intiator to afford the desiredbromomethylphenyl thiophenes and bromomethylphenyl furans. ##STR64##

An alternative synthesis for the desired 3-(4-bromomethylphenyl)thiophenes and furans necessary for the constuction of 2,3-disubstitutedthiophenes and furans of the 2,3-disubstituted thiophenes and furans(Y=O or S) of formula I, where X¹ --X² --X³ --X⁴ =--CR¹¹ --CR¹²--S--CZ-- and Z=SO₂ NHCOR⁷ and R¹¹ =R¹² =H, is illustrated in schemeII-5, 2-Thiophenesulfonyl chloride and 2-furansulfonyl chloride areconverted to their respective tbutyl sulfonamides by reaction withtbutylamine in CH₂ Cl₂. The dianion is generated with two equivalents ofa strong base such as nBuLi or tBuLi; this is followed by quenching withTMSCl, addition of another equivalent of strong base and finallyquenching with Br₂. These bromo derivatives are coupled withp-tolyltrimethyl tin in the presence of a catalytic amount of palladium(0) in refluxing toluene or hot DMF. Benzylic bromination usingN-bromosuccinimide provides the desired bromomethylphenyl thiophenes andbromomethylphenyl furans. ##STR65##

The desired methanesulfonylmethylphenyl thiophenes and furans necessaryfor the constuction of 2,3-disubstituted thiophenes and furans (Y=O orS) of formula I, where X¹ --X² --X³ --X⁴ =--S--CH--CH--CZ-- andZ=tetrazolyl, are prepared as illustrated in scheme II-6.3-Cyanothiophene and 3-cyanofuran are converted to their respectiveprotected tetrazole derivatives by reaction with trimethyltin azide inrefluxing toluene followed by treatment with dilute mineral acid andfinally protection with triphenylmethyl chloride in the presence oftriethyl amine. Generation of the anion at the 2-position, using astrong base such as nBuLi, followed by quenching with trimethyltinchloride provides the desired protected tetrazolylaryltrimethyltinderivative. Palladium catalyzed cross coupling with methylp-iodiobenzoate using Pd(PPH₃)₂ Cl₂ or Pd(PPh₃)₄ in refluxing toluene orhot DMF followed by lithium aluminum hydride reduction and treatment ofthe resultant alcohol with methanesulfonyl chloride and triethyl amineprovides the desired methanesulfonylmethylphenyl thiophenes andmethanesulfonylmethylphenyl furans. ##STR66##

The desired bromomethylphenyl thiophenes and furans necessary for theconstruction of 2,3-disubstituted thiophenes and furans (Y=O or S) orformula I, where X¹ --X² --X³ --X⁴ =--S--CH--CH--CZ-- and Z=SO₂ NHCOR⁷,are prepared are illustrated in scheme II-7. 2,5-Dibromothiophene or2,5-dibromofuran can be chlorosulfonylated with chlorosulfonic acid toprovide sulfonyl chloride 7a. Reaction with tbutylamine, followed byreduction with zinc in acetic acid affords 7c. Dianion generation, usinga strong base (nBuLi or tBuLi), followed by quenching with Br₂, providesbromo compound 7d. Palladium catalyzed coupling of p-tolytrimethyltinwith the newly prepared arylbromide in hot DMF or refluxing tolueneprovides biaryl compound 7e. Treatment of 7e with N-bromosuccinimide inthe presence of a catalytic amount of AIBN or benzoylperoxide inrefluxing carbontetrachloride or benzene provides the desiredbromomethylphenyl thiophenes and bromomethylphenyl furans. ##STR67##

The desired antagonists of formula I (Z=tetrazolyl) are prepared, asillustrated in scheme II-8, by deprotonation of the desired heterocycle,for example 2 -butyl-6-methylquinazolin-4(1H)-one, with sodium hydridein dimethylformamide to generate the sodium salt, 8a. Alkylation of thesodium salt with a derivative containing a good leaving group such asthe bromomethyl derivative or the methanesulfonyl derivative, isfollowed by deprotection to provide the free tetrazole.

The desired antagonists of formula I (Z═SO₂ NHCOR⁷) are prepared, asillustrated in scheme II-9, by deprotonation of the desired heterocycle,for example 2-butyl-6-methylquinazolin-4-(1H)-one, with sodium hydridein dimethylformamide to generate the sodium salt. Alkylation of thesodium salt with the bromomethyl derivative or the methanesulfonylderivative followed by deprotection with trifluoroacetic acid andcoupling with an activated acid derivative completes the synthesis ofthe sulfonamide containing thiophene antagonists.

The desired antagonist of formula I, where X¹ --X² --X³ --X⁴ ═--CR¹¹--CR¹² --S--CZ--, Z═SO₂ HNCOR⁷, R¹¹ and R¹² are joined to form an arylring, and R⁷ ═Ph, is prepared as illustrated in scheme II-10 bydeprotonation of the desired heterocycle, for example2-butyl-6-methylquinazolin-4(1H)-one, with sodium hydride in dimethylformamide to generate the sodium salt. Alkylation of the sodium saltwith the benzothiophene derivative, compound 4e, which is prepared usingthe chemistry illustrated in scheme II-4, affords 10a. As in schemeII-9, deprotection with TFA is followed by coupling to an activated acidderivative to complete the synthesis. ##STR68##

An alternative synthesis for the bromomethylphenyl thiophenes necessaryfor the construction of substituted thiophenes of formula I, where X¹--X² --X³ --X⁴ ═--CH═C(R¹²)--S--CZ═ and Z═SO₂ NHCOR¹⁴ is illustrated inscheme II-11. Alkylthiophene 11a is cleanly prepared by alkylation ofthe dianion of 2-(tbutylsulfonamido)thiophene, generated with twoequivalents of BuLi or LDA, with an appropriate alkylhalide (R¹² X). Asecond dianion generation, followed by quenching first withtriisopropylborate, then with 2N HCl, affords the boronic acidderivative 11b. Palladium catalyzed coupling of the 11b with4-bromobenzyl alcohol provides 11c. The benzyl alcohol is then cleanlyconverted to the corresponding bromide (11d) with PB₃ or CBr₄ /PPh₃.

This benzyl bromide is used in place of compound 2d in scheme II-9 tocomplete the synthesis of the antagonist.

Scheme II-12 illustrates a more convergent approach to the synthesis ofsubstituted thiophenes of formula I, where X¹ --X² --X³ --X⁴═--CH═C(R¹²)--S--CZ═and Z═SO₂ HNCOR¹⁴. Palladium catalyzed coupling ofboronic acid 11b with a 4-bromobenzyl derivative, such as 12a, providesa nearly complete antagonist. Completion of the antagonist from 12b isillustrated in scheme II-9. ##STR69##

An alternative synthesis for the bromomethylphenyl thiophenes necessaryfor the construction of substituted thiophenes of formula I, where X¹--X² --X³ --X⁴ ═--CH═C(R¹²)--S--CZ═ and Z=tetrazolyl is illustrated inscheme II-13. alkylthiophene 13a is prepared by alkylation of the2-(triphenylmentyltetrazolyl)-thiophene with an appropriate alkylhalide(R¹² X). Directed metallation with BuLi, is followed by quenching withtriisopropylborate. The borate ester is gently hydrolyzed with diluteacetic acid to afford the boronic acid derivative 13b. Palladiumcatalyzed coupling of 13b with 4-bromobenzyl alcohol provides 13c. Thebenzyl alcohol is then cleanly converted to the corresponding bromide(13d) with PBr₂ or CBr₄ /PPh₃.

This benzyl bromide is used in place of compound 2d in scheme II-9 tocomplete the synthesis of the antagonist.

Scheme II-14 illustrates a more convergent approach to the synthesis ofsubstituted thiophenes of formula I, where X¹ --X² --X³ --X⁴═--CH═C(R¹²)--S--CZ═ and Z=tetrazolyl. Palladium catalyzed coupling ofboronic acid 13b with a 4-bromobenzyl derivative, such as 12a, providesa nearly complete antagonist. Completion of the antagonist from 14b isillustrated in scheme II-9. ##STR70##

Compounds of formula I, where X¹ --X² --X³ --X⁴ ═--CH═C(R¹²)--S--CZ═,Z═SO₂ NHCOR¹⁴ and R¹² ═CH₂ NR^(2a) R^(2a) best prepared as illustratedin scheme II-15. Palladium catalyzed coupling of boronic acid 11b (R¹²=TMS) with 4-bromotoluene provides 15a. Fluoride mediated removal of thetrimethylsilyl group is cleanly accomplished using nBu₄ F in THF.Dianion formation of 15b followed by quenching with a formylating agent,such as DMF, provides the formyl derivative after acid work-up. Benzylicbromination is followed by coupling to the sodium salt of a heterocyclesuch as a substituted quinazolinone, triazolinone or pyrimidinone toafford 15e. Reductive amination of the aldehyde is then followed by theusual reactions to complete the synthesis of the antagonist.

Alternatively, bromomethyl derivative 16e (scheme II-16) can be preparedand coupled to a heterocycle using previously described syntheticmethods. NBS bromination of 2-methyl-5-(tbutylsulfonamido)thiopheneprovides bromomethyl derivative 16a. The bromomethyl derivative is thenreacted with excess amine (HNR^(2a) R^(2a)), such as morpholine, toafford 16b. Reaction of 16b with two equivalents of a strong base, suchas LDA or nBuLi, is followed by addition of bromine to provide 16c.Palladium catalyzed coupling of 16c with4-(t-butyldimethylsilyloxymethyl)-phenyltrimethyltin provides compound16d. Silyl removal followed by conversion to the corresponding bromideaffords 16e. ##STR71##

Antagonists of formula I, where the heterocycle is a 2-alkyl-8-nitrogensubstituted quinazoline-4(1H)-one, X¹ --X² --X³ --X⁴ is --CH═CR¹²--S--CZ═, and Z═SO₂ NHCOR¹⁴ are best prepared by the synthetic routeoutline in Scheme II-17. Hydrogenation of the 6-nitroquinazolinonecleanly produces the desired amino derivative. Acylation with anappropriate acid chloride in the presence of pyridine providedderivative 17c. Coupling of 17c with lid in DMF using K₂ CO₃ affords thecoupled product 17d. Deprotection with TFA is followed by acylation,with either and acid chloride (R¹⁴ COCl) in the presence of pyridine oran acid (R¹⁴ CO₂ H) after prior activation with CDI, to complete theantagonist. ##STR72##

In some instances functionalization of the quinazolinone is bestperformed after coupling with the bromomethylphenylthiophene derivative(11d). This is most efficiently accomplished using the synthetic routeoutlined in Scheme II-18. Alkylation of 2-propyl-6-nitroquinazolinonewith benzylbromide derivative 11d using K₂ CO₃ in DMF provides 18a.Deprotection with TFA and hydrogenation provides the amino sulfonamidederivative 18b. The amine function can be reacted with a variety ofelectrophiles, such as an isocyanate, to afford, in this case, the ureaderivative 18c. Acylation of the sulfonamide, using procedurespreviously described, completes the synthesis of the antagonist.##STR73##

The compounds of this invention form salts with various inorganic andorganic acids and bases which are also within the scope of theinvention. Such salts include ammonium salts, alkali metal salts likesodium and potassium salts, alkaline earth metal salts like the calciumand magnesium salts, salts with organic bases; e.g., dicyclohexylaminesalts, N-methyl-D-glucamine, salts with amino acids like arginine,lysine, and the like. Also, salts with organic and inorganic acids maybe prepared; e.g., HCl, HBr, H₂ SO₄, H₃ PO₄, methane-sulfonic,toluenesulfonic, maleic, fumaric, camphorsulfonic. The non-toxic,physiologically, acceptable salts are preferred, although other saltsare also useful; e.g., in isolating or purifying the product.

The salts can be formed by conventional means such as by reacting thefree acid or free base forms of the product with one or more equivalentsof the appropriate base or acid in a solvent or medium in which the saltis insoluble, or in a solvent such as water which is then removed invacuo or by freeze-drying or by exchanging the cations of an existingsalt for another cation on a suitable ion exchange resin.

Angiotensin II (AII) is a powerful arterial vasoconstrictor, and itexerts its action by interacting with specific receptors present on cellmembranes. The compounds described in the present invention act ascompetitive antagonists of AII at the receptors. In order to identifyAII antagonists and determine their efficacy in vitro, the following twoligand-receptor binding assays were established.

Receptor binding assay using rabbit aortae membrane preparation

Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) weresuspended in 5 mM Tris-0.25M Sucrose, pH 7.4 buffer (50 mL) homogenized,and then centifuged. The mixture was filtered through a cheesecloth andthe supernatant was centrifuged for 30 minutes at 20,000 rpm at 4° C.The pellet thus obtained was resuspended in 30 mL of 50 mM Tris-5 mMMgCl₂ buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mLBacitracin and the suspension was used for 100 assay tubes. Samplestested for screening were done in duplicate. To the membrane preparation(0.25 mL) there was added ¹²⁵ I-Sar¹ Ile¹ -angiotensin II [obtained fromNew England Nuclear] (10 mL; 20,000 cpm) with or without the test sampleand the mixture was incubated at 37° C. for 90 minutes. The mixture wasthen diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4 (4mL) andfiltered through a glass fiber filter (GF/B Whatman 2.4" diameter). Thefilter was soaked in scintillation cocktail (10 mL) and counted forradioactivity using Packard 2660 Tricarb liquid scintillation counter.The inhibitory concentration (IC₅₀) of potential AII antagonist whichgives 50% displacement of the total specifically bound ¹²⁵ I-Sar¹ Ile⁸-angiotensin II was presented as a measure of the efficacy of suchcompounds as AII antagonists.

Receptor assay using Bovine adrenal cortex preparation

Bovine adrenal cortex was selected as the source of AII receptor.Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended inTris HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate wascentrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded andpellets resuspended in buffer [Na₂ HPO₄ (10 mM)-NaCl (120 mM)-disodiumEDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF) (0.1 mM)].(For screening of compounds, generally duplicates of tubes are used). Tothe membrane preparation of (0.5 mL) there was added ³ H-angiotensin II(50 mM) (10 mL) with or without the test sample and the mixture wasincubated at 37° C. for 1 hour. The mixture was then diluted with Trisbuffer (4 mL) and filtered through a glass fiber filter (GF/B Whatman2.4" diameter). The filter was soaked in scintillation cocktail (10 mL)and counted for radioactivity using Packard 2660 Tricarb liquidscintillation counter. The inhibitory concentration (IC₅₀) of potentialAII antagonist which gives 50% displacement of the total specificallybound ³ H-angiotensin II was presented as a measure of the efficacy ofsuch compounds as AII antagonists.

The potential antihypertensive effects of the compounds described in thepresent invention may be evaluated using the methodology describedbelow: Male Charles river Sprague-Dawley rats (300-375 gm) wereanesthetized with methohexital (Brevital: 50 mg/kg i.p.) and the tracheawas cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mmthick, 150 mm long) was inserted into the orbit of the right eye anddown the spinal column. The rats were immediately placed on a HarvardRodent Ventilator (rate--60 strokes per minutes, volume--1.1 cc per 100grams body weight). The right carotid artery was ligated, both left andright vagal nerves were cut, and the left carotid artery was cannulatedwith PE 50 tubing for drug administration, and body temperature wasmaintained at 37° C. by a thermostatically controlled heating pad whichreceived input from a rectal temperature probe. Atropine (1 mg/kg i.v.)was then administered, and 15 minutes later propranolol (1 mg/kg i.v.).Thirty minutes later angiotensin II or other agonists were administeredintravenously at 30 minute intervals and the increase in the diastolicblood pressure was recorded before and after drug or vehicleadministration.

Using the methodology described above, representative compounds of theinvention were evaluated and found to exhibit an activity of at leastIC₅₀ <50 mM thereby demonstrating and confirming the utility of thecompounds of the invention as effective AII antagonists.

Thus, the compounds of the invention are useful in treatinghypertension. They are also of value in the management of acute andchronic congestive heart failure, in the treatment of secondaryhyperaldosteronism, primary and secondary pulmonary hyperaldosteronism,primary and secondary pulmonary hypertension, renal failure and renalvascular hypertension, and in the management of vascular disorders suchas migraine or Raynaud's disease. The application of the compounds ofthis invention for these and similar disorders will be apparent to thoseskilled in the art.

The compounds of this invention are also useful to treat elevatedintraocular pressure and can be administered to patients in need of suchtreatment with typical pharmaceutical formulations such as tablets,capsules, injectables, as well as topical ocular formulations in theform of solutions, ointments, inserts, gels and the like.

Pharmaceutical formulations prepared to treat intraocular pressure wouldtypically contain about 0.1% to 15% by weight, and preferably 0.5% to2.0% by weight of a compound of this invention.

In the management of hypertension and the clinical conditions notedabove, the compounds of this invention may be utilized in compositionssuch as tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike. The compounds of this invention can be administered to patients(animals and human) in need of such treatment in dosages that willprovide optimal pharmaceutical efficacy. Although the dose will varyfrom patient to patient depending upon the nature and severity ofdisease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize, the dosage range will generally be about 1 to1000 mg per patient per day which can be administered in single ormultiple doses. Perferably, the dosage range will be about 2.5 to 250 mgper patient per day; more preferably about 2.5 to 75 mg per patient perday.

The compounds of this invention can also be administered in combinationwith other antihypertensives and/or diuretics and/or angiotensinconverting enzyme inhibitors and/or calcium channel blockers. Forexample, the compounds of this invention can be given in combinationwith such compounds as amiloride, atenolol, bendroflumethiazide,chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates andcryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate,hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprololtartate, methylclothiazide, methyldopa, methyldopate hydrochloride,minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol,rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside,spironolactone, timolol maleate, trichlormethiazide, trimethophancamsylate, benzthiazide, quinethazone, ticrynafan, triamterene,acetazolamide, aminophylline, cyclothiazide, ethacrynic acid,furosemide, merthoxylline procaine, sodium ethacrynate, captopril,delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium,lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide,zofenopril calcium, diflunisal, diltiazem, felodipine, nicardipine,nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and thelike, as well as admixtures and combinations thereof.

Typically, the individual daily dosages for these combinations can rangefrom about one-fifth of the minimally recommended clinical dosages tothe maximum recommended levels for the entities when they are givensingly.

To illustrate these combinations, one of the angiotensin II antagonistsof this invention effective clinically in the 2.5-250 milligrams per dayrange can be effectively combined at levels at the 0.5-250 milligramsper day range with the following compounds at the indicated per day doserange: hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg),ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),propranolol (20-480 mg), timolol maleate (5-60 mg), methyldopa (65-2000mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60mg). In addition, triple drug combinations of hydrochlorothiazide(15-200 mg) plus amiloride (5-20 mg) plus angiotensin II antagonist ofthis invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plustimolol maleate (5-60) plus an angiotensin II antagonist of thisinvention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine(5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250mg) are effective combinations to control blood pressure in hypertensivepatients. Naturally, these dose rangers can be adjusted on a unit basisas necessary to permit divided daily dosage and, as noted above, thedose will vary depending on the nature and severity of the disease,weight of patient, special diets and other factors.

Typically, these combinations can be formulated into pharmaceuticalcompositions as discussed below.

About 1 to 100 mg of compound or mixture of compounds of Formula I or aphysiologically acceptable salt is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, flavor, etc., in a unit dosage form as called for byaccepted pharmaceutical practice. The amount of active substance inthese compositions or preparations is such that a suitable dosage in therange indicated is obtained.

Illustrative of the adjuvants which can be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asmicrocrystalline cellulose; a disintegrating agent such as corn starch,pregelatinized starch, alginic acid and the like; a lubricant such asmagnesium stearate; a sweetening agent such as sucrose, lactose orsaccharin; a flavoring agent such as peppermint, oil of wintergreen orcherry. When the dosage unitform is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier such as fattyoil. Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile compounds for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection, a naturallyoccuring vegetable oil like sesame oil, coconut oil, peanut oil,cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, preservatives, antioxidants and the like can beincorporated as required.

The compounds of this invention are also useful to treat elevatedintraocular pressure and can be administered to patients in need of suchtreatment with typical pharmaceutical formulations such as tablets,capsules, injectables, as well as topical ocular formulations in theform of solutions, ointments, inserts, gels and the like. Pharmaceuticalformulations prepared to treat intraocular pressure would typicallycontain about 0.1% to 15% by weight, and preferably 0.5% to 2.0% byweight of a compound of this invention.

Thus, the compounds of the invention are useful in treatinghypertension. They are also of value in the management of acute andchronic congestive heart failure, in the treatment of secondaryhyperaldosteronism, primary and secondary pulmonary hypertension, renalfailure such as diabetic nephropathy, glomerulonephritis, scleroderma,and the like, renal vascular hypertension, left ventricular dysfunction,diabetic retinopathy, and in the management of vascular disorders suchas migraine or Raynaud's disease. The application of the compounds ofthis invention for these and similar disorders will be apparent to thoseskilled in the art.

The useful central nervous system (CNS) activities of the compounds ofthis invention are demonstrated and exemplified by the ensuing assays.

COGNITIVE FUNCTION ASSAY

The efficacy of these compounds to enhance cognitive function can bedemonstrated in a rat passive avoidance assay in which cholinomimeticssuch as physostigmine and nootropic agents are known to be active. Inthis assay, rats are trained to inhibit their natural tendency to enterdark areas. The test apparatus used consists of two chambers, one ofwhich is brightly illuminated and the other is dark. Rats are placed inthe illuminated chamber and the elapsed time it take for them to enterthe darkened chamber is recorded. On entering the dark chamber, theyreceive a brief electric shock to the feet. The test animals arepretreated with 0.2 mg/kg of the muscarinic antagonist scopolamine withdisrupts learning or are treated with scopolamine and the compound whichis to be tested for possible reversal of the scopolamine effect.Twenty-four hours later, the rats are returned to the illuminatedchamber. Upon return to the illuminated chamber, normal young rats whohave been subjected to this training and who have been treated only withcontrol vehicle take longer to re-enter the dark chamber than testanimals who have been exposed to the apparatus but who have not receiveda shock. Rats treated with scopolamine before training do not allow thishesitation when tested 24 hours later. Efficacious test compounds canovercome the disruptive effect on learning which scopolamine produces.Typically, compounds of this invention should be efficacious in thispassive avoidance assay in the dose range of from about 0.1 mg/kg toabout 100 mg/kg.

ANXIOLYTIC ASSAY

The anxiolytic activity of the invention compounds can be demonstratedin a conditioned emotional response (CER) assay. Diazepam is aclinically useful anxiolytic which is active in this assay. In the CERprotocol, male Sprague-Dawley rats (250-350 g) are trained to press alever on a variable interval (VI) 60 second schedule for foodreinforcement in a standard operant chamber over weekly (five days perweek) training sessions. All animals then receive daily 20 minuteconditioning sessions, each session partitioned into alternating 5minute light (L) and 2 minute dark (D) periods in a fixed L1D1L2D2L3sequence. During both periods (L or D), pressing a lever delivers foodpellets on a VI 60 second schedule: in the dark (D), lever presses alsoelicit mild footshock (0.8 mA, 0.5 sec) on an independent shockpresentation schedule of VI 20 seconds. Lever pressing is suppressedduring the dark periods reflecting the formation of a conditionedemotional response (CER).

Drug testing in this paradigm is carried out under extinctionconditions. During extinction, animals learn that responding for food inthe dark is no longer punished by shock. Therefore, response ratesgradually increase in the dark periods and animals treated with ananxiolytic drug show a more rapid increase in response rate than vehicletreated animals. Compounds of this invention should be efficacious inthis test procedure in the range of from about 0.1 mg/kg to about 100mg/kg.

DEPRESSION ASSAY

The antidepressant activity of the compounds of this invention can bedemonstrated in a tail suspension test using mice. A clinically usefulantidepressant which serves as a positive control in this assay isdesipramine. The method is based on the observations that a mousesuspended by the tail shows alternate periods of agitation andimmobility and that antidepressants modify the balance between these twoforms of behavior in favor of agitation. Periods of immobility in a 5minute test period are recorded using a keypad linked to a microcomputerwhich allows the experimenter to assign to each animal an identity codeand to measure latency, duration and frequency of immobile periods.Compounds of this invention should be efficacious in this test procedurein the range of from about 0.1 mg/kg to about 100 mg/kg.

SCHIZOPHRENIA ASSAY

The antidopaminergic activity of the compounds of this invention can bedemonstrated in an apomorphine-induced sterotypy model. A clinicallyuseful antiphyschotic drug that is used as a positive control in thisassay is haloperidol. The assay method is based upon the observationthat stimulation of the dopaminergic system in rats produces stereotypedmotor behavior. There is a strong correlation between the effectivenessof classical neuroleptic drugs to block apomorphine-induced sterotypyand to prevent schizophrenic symptoms. Stereotyped behavior induced byapomorphine, with and without pretreatment with test compounds, isrecorded using a keypad linked to a microcomputer. Compounds of theinvention should be efficacious in this assay in the range of from about0.1 mg/kg to about 100 mg/kg.

In the treatment of the clinical conditions noted above, the compoundsof this invention may be utilized in compositions such as tablets,capsules or elixirs for oral administration, suppositories for rectaladministration, sterile solutions or suspensions for parenteral orintramuscular administration, and the like. The compounds of thisinvention can be administered to patients (animals and human) in need ofsuch treatment in dosages that will provide optimal pharmaceuticalefficacy. Although the dose will vary from patient to patient dependingupon the nature and severity of disease, the patient's weight, specialdiets then being followed by a patient, concurrent medication, and otherfactors which those skilled in the art will recognize, the dosage rangewill generally be about 5 to 6000 mg. per patient per day which can beadministered in single or multiple doses. Perferably, the dosage rangewill be about 10 to 4000 mg. per patient per day; more preferably about20 to 2000 mg. per patient per day.

In order to obtain maximal enhancement of cognitive function, thecompounds of this invention may be combined with othercognition-enhancing agents. These include acetylcholinesteraseinhibitors such as heptylphysostigmine and tetrahydroacridine (THA;tacrine), muscarinic agonists such as oxotremorine, inhibitors ofangiotensin-converting enzyme such as octylramipril, captopril,ceranapril, enalapril, lisinopril, fosinopril and zofenopril,centrally-acting calcium channel blockers and a nimodipine, andnootropic agents such as piracetam.

In order to achieve optimal anxiolytic activity, the compounds of thisinvention may be combined with other anxiolytic agents such asalprazolam, lorazepam, diazepam, and busipirone.

In order to achieve optimal antidepressant activity, combinations of thecompounds of this invention with other antidepressants are of use. Theseinclude tricyclic antidepressants such as nortriptyline, amitryptylineand trazodone, and monoamine oxidase inhibitors such as tranylcypromine.

In order to obtain maximal antipsychotic activity, the compounds of thisinvention may be combined with other antipsychotic agents such aspromethazine, fluphenazine and haloperidol.

The following examples illustrate the preparation of the compounds ofFormula I and their incorporation into pharmaceutical compositions andas such are not to be considered as limiting the invention set forth inthe claims appended hereto.

PREPARATION OF 2-ALKYL-QUINAZOLIN-4-(1H)-ONES EXAMPLE 12-Butyl-6-methylquinazolin-4(1H)-one

To a solution of 3.0 g (20 mmol) of 2-amino-5-methylbenzoic acid in 20mL of dry DMF at 0° C. was added 200 mg of DMAP followed by 6.07 g (60mmol) of triethyl amine and 5.02 g (40 mmol) of valeryl chloride. Theresulting mixture was stirred at 0° C. for 30 minutes. The mixture washeated to 110° C. and monitored by TLC for the formation of theintermediate quinoxazolone (rf=0.8, 40% EtOAc/hexane). Followingcomplete formation of the intermediate 10 g (100 mmol) of NH₄ CO₃ wasadded cautiously. Heating was continued to ensure consumption of thequinoxazolone and formation of the polar (rf=0.4, 40% EtOAc/hexane)quinazolin-4(1H-one. The reaction mixture was concentrated in vacuo andthe residue was taken up in 50 mL of ether and 50 mL of water. Themixture was filtered and the filtrate discarded after washing theresidue with 20 mL of water. The residue was recrystallized from MeOH togive 1.07 g (5 mmol) of a white crystaline solid. 25% yield overall. ¹H-NMR (CDCl₃): 0.94 (t, 3H, J=6.7 Hz), 1.50 (m, 2H), 1.83 (m, 2H), 2.49(s, 3H), 2.78 (t, 2H), 7.60 (m, 2H), 8.05 (m, 1H). Anal (C₁₃ H₁₆ N₂ O),C, H, N.

EXAMPLE 2 6-Methyl-2-propylquinazoline-4(1H)-one

The 2-propyl derivative was prepared in the identical fashion as the2-butyl derivative through the use of butyryl chloride in place ofvaleryl chloride. The product was recrystallized from hexane/acetone togive white crystals. 32% yield. ¹ H-NMR (CDCl₃): 11.51 (bs, 1H), 8.08(s, 1H), 7.60 (s, 2H), 2.78 (3 line m, 2H), 2.01 (s, 3H), 1.92 (m, 2H),1.09 (t, 3H).

EXAMPLE 3 2-Butyl-7-methylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-4-methylbenzoic acid. The product was recrystallized from MeOHrecovering 0.91 g (4.2 mmol). 21% yield overall. ¹ H-NMR (CDCl₃): 0.99(t, 3H, J=7.4 Hz), 1.49 (m, 2; H), 1.86 (m, 2H), 2.50 (s, 3H), 2.76 (t,2H, J=7.81 Hz), 7.28 (d, 1H, J=8.3 Hz), 7.49 (s, 1H), 8.15 (d, 1H, J=8.3Hz). Anal (C₁₃ H₁₆ N₂ O), C, H, N.

EXAMPLE 4 2-Butyl-naphtho[2,3-e]quinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-aminonaphthoic acid. Product was recrystallized from MeOH. Acontaminant co-crystallizes with the desired product. The contaminant is25% of the product by ¹ H-NMR. Recovered 1.6 g (59% yield). ¹ H-NMR(CDCl₃): 0.97 (t, 3H, J=7.3 Hz), 1.42 (m, 2H), 1.75 (m, 2H), 2.48 (t,2H, J=7.4 Hz), 7.42 (t, 1H, J=7.8 Hz), 7.54 (t, 1H, J=8.3 Hz), 7.77 (d,1H, J=7.8 Hz), 7.82 (d, 1H, J=8.31 Hz), 8.07 (s, 1H), 9.08 (s, 1H),10.89 (bs, 1H).

EXAMPLE 5 2-Butyl-5-methylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-6-methylbenzoic acid on a 16 mmol scale. The concentratedreaction mixture was diluted with 50 mL ether and 50 mL H₂ O. Themixture was agitated for several minutes and then filtered in vacuo. Onfiltration further crystalline material formed in the filtrate. Thefiltrate was filtered again. This procedure was repeated a further twotimes. The precipitates were collected and combined. The ethereal phasewas decanted from the aqueous phase, and concentrated to 15 mL. 25 mL ofhexanes was then added and the mixture filtered. The combinedprecipitates were recrystallized from MeOH/H₂ O to give 0.73 g (3.37mmol) of fluffy white crystals. 21% yield. ¹ H-NMR (CDCl₃): 0.98 (t, 3H,J=7.38 Hz), 1.48 (m, 2H), 1.87 (m, 2H), 2.75 (dd, 2H, J=8.09 Hz), 2.89(s, 3H), 7.20 (d, J=6.73 Hz), 7.56 (m, 2H), 11.68 (bs, 1H).

EXAMPLE 6 2-Butyl-6,8-dimethylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-5,8-dimethylbenzoic acid on a 12 mmol scale. The productcollected from filtration of the ether/water mixture was recrystalizedfrom MeOH. ¹ H-NMR and TLC indicated that the product isolated was a 50%mixture of the desired quinazoline and a contaminant. An aliquot of 0.5g of this material was concentrated onto 5 mL of flash silica andapplied to the surface of a flash chromatography column. The column waseluted with 60% EtOAc/hexanes. The first eluted compound (0.14 g) wascollected as a TLC homogeneous sample of the desired product. ¹ H-NMR(CDCl₃): 0.99 (t, 3H, J=7.32 Hz), 1.48 (m, 2H), 1.85 (m, 2H), 2.44 (s,3H), 2.58 (s, 3H), 2.75 (dd, 2H, J=7.87, 7.87 Hz), 7.43 (s, 1H), 7.91(s, 1H), 10.70 (bs, 1H).

EXAMPLE 7 2-Butyl-8-methylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-6-methylbenzoic acid on a 1 mmol scale. The concentratedreaction mixture was diluted with 20 mL ether/20 mL H₂ O. The mixturewas filtered. The ethereal phase was seperated, dried (MgSO₄), filteredand concentrated. The residue was flash chromatographed over silicaeluting with 50% EtOAc/hexanes to give rise to 48 mg (0.22 mmol) of afluffy yellow solid. 22% yield. ¹ H-NMR (CDCl₃): 1.02 (t, 3H), 1.52 (m,2H), 1.88 (m, 2H), 2.62 (s, 3H), 2.79 (dd, 2H), 7.35 (dd, 1H), 1.61 (d,1H), 8.12 (d, 1H). FABMS: 2.17 (M⁺ +1) calc for C₁₃ H₁₆ N₂ O.

EXAMPLE 8 2-Butyl-6-isopropylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-5-isopropylbenzoic acid on a 16 mmol scale. The concentratedreaction mixture was partitioned between 20 mL water and 20 mL of ether.A fine white precipitate was removed by filtration and recrystallizedfrom MeOH/water. The first crop gave rise to 0.56 g of fluffy whitecrystals. ¹ H-NMR (CDCl₃): 0.99 (t, 3H, J=7.3 Hz), 1.32 (d, 6H, J=6.89Hz), 1.48 (m, 2H), 1.85 (m, 2H), 2.77 (3 line m, 2H, J=7.9 Hz), 3.06 (m,1H), 7.65 (m, 2H), 8.11 (s, 1H), 11.22 (bs, 1H). FABMS: 245 (M⁺ +1) calcfor C₁₅ H₂₀ N₂ O.

EXAMPLE 9 2-Butyl-6-thiomethylquinazolin-4(1H)-one

Same procedure as that described in Example 1. However on addition ofether/water to the reaction mixture a precipitate of the quinazolinonewas not formed. The aqueous phase was extracted with ether and thecombined ethereal extracts were washed with brine and dried over MgSO₄.The mixture was filtered and concentrated in vacuo to give a mixture ofthe desired product and 2-(N-valeroyl-amino)-5-thiomethylbenzamide. Thismixture was heated with 2 equivalents of 1N NaOH solution in water at100° C. until a clear solution was obtained. The solution was cooled,acidified, and filtered to give a pale yellow precipitate. The productwas recrystalized from MeOH to give a 73% overall yield of the titlecompound. ¹ H-NMR (CDCl₃ -300 MHz): 1.00 (t, 3H, J=7.3 Hz), 1.50 (m,2H), 1.86 (m, 2H), 2.58 (s, 3H), 2.76 (3line m, 2H, J=7.9 Hz), 7.62 (m,2H), 8.03 (d, 1H, J=1.9 Hz), 11.11 (bs, 1H).

EXAMPLE 10 2-Butyl-6-nitroquinazolin-4(1H)-one

To a mixture of 326 mg (2 mmol) of 2-cyano-4-nitroaniline in 10 mL ofCH₂ Cl₂ at 0° C. was added 0.34 mL (2.4 mmol) of triethylamine and 25 mgof DMAP. To this mixture was added 0.26 ml of valeryl chloride dropwise.The reaction mixture was allowed to warm to room temperature over 1.5hours and then concentrated in vacuo. The residue was dissolved in 40 mlof EtOAc and washed with 25 ml of water, 25 ml of saturated NaHCO₃ and25 ml of brine. The organic phase was dried over Na₂ SO₄, filtered andconcentrated. The residue (0.46 g) was purified by flash chromatography.The residue was absorbed onto 0.6 g of silica which was applied to thesurface of a 5.5"×0.75" silica flash chromatography column. The productwas eluted with 20% EtOAc/hexanes to give 0.21 g ofN-valeryl-2-cyano-4-nitro-anilide (44% yield). 0.1 g (0.42 mmol) of theamide was dissolved in 1.5 mL of MeOH. To this solution was added 138 μLof a 30% hydrogen peroxide solution followed by 330 μL of a 3N NaOHsolution. The solution was refluxed for 1.5 hours, cooled andconcentrated in vacuo. The residue was dissolved in 10 mL of water.Dropwise addition of a saturated solution of NH₄ Cl caused the productto precipitate out as 90 mg (0.36 mmol) of a yellow powder. (87% yield.¹ H-NMR (CDCl₃): 1.02 (t, 3H, J=7.32 Hz), 1.52 (m, 2H), 1.90 (m, 2H),2.82 (dd, 2H, J=8.03 Hz), 7.82 (d, 1H, J=9.01 Hz), 8.56 (dd, 1H, J=2.6,8.9 Hz), 9.14 (d, 1H, J=2.71 Hz).

EXAMPLE 11 2-Butylquinazolin-4(1H)-one

To a solution of 500 mg 2-aminobenzonitrile (4.23 mmol), 514 mgtriethylamine (5.08 mmol), and 50 mg DMAP (0.41 mmol) in 6 mL CH₂ Cl₂ at0° C. was added 562 mg valeryl chloride (4.66 mmol) dropwise over1minute. The mixture was warmed to room temperature and stirred fortwenty minutes. The mixture was then diluted with water and brine andthen was extracted three times with ether. The combined organic materialwas dried over MgSO₄, stripped of solvent in vacuo, and was purified byflash chromatography eluting with 20% ethyl acetate in hexane to give2-valerylamido-benzonitrile. R_(f) 0.22 in 20% ethyl acetate in hexane.¹ H-NMR (300 MHz, CDCl₃): 8.42 (d, 1H), 7.60-7.01 (m, 2H), 6.72 (m, 1H),4.40 (br s, 1H), 2.46 (t, 2H), 1.74 (m, 2H), 1.43 (m, 2H), 0.97 (t, 3H).

To a solution of 5.1 g of the amide in 90 mL methanol were added 21 mL3N NaOH and 10 ml 30% H₂ O₂ at room temperature. The mixture wasrefluxed for 30 minutes and concentrated in vacuo. Water and sat. NH₄ Clwas added and the mixture extracted 3 times with ether. The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo and the residue was recrystallized from hexane/acetone to give twocrops of the product as white needles. 2.2 g, 43% yield. R_(f) : 0.16 in20% EtOAc in CH₂ Cl₂. ¹ H-NMR (CDCl₃): 8.29 (m, 1H), 7.81-7.68 (m, 2H),7.47 (m, 1H), 2.79 (3 line m, 2H), 1.87 (m, 2H), 1.51 (m, 2H), 1.00 (t,1H).

EXAMPLE 12 6-Bromomethyl-2-butylquinazolin-4(1H)-one

To a suspension of 2.6 g (12 mmol) of the product of Example 2 in 100 mLof dry CCl₄ was added 2.56 g of N-bromosuccinimide followed by 200 mg ofbenzoyl peroxide. The reaction mixture was heated to reflux for 45minutes at which time a precipitate formed throughout. The reactionmixture was concentrated in vacuo and the residue partitioned between150 mL of EtOAc and 100 mL of water. The mixture was shaken and thenfiltered to give 1.59 g of the title compound (45% yield). The filtratewas seperated into two phases and the organic phases was washed with 75mL of sat. NaHCO₃ solution followed by 75 mL of water and 75 mL ofbrine. The organic phase was dried over MgSO₄, filtered and the filtratewas concentrated in vacuo. The residue was purified by recrystalizationfrom EtOAc to give 0.52 g (1.76 mmol) of the same product as wasrecovered above. Total yield 60%. ¹ H-NMR (CDCl₃): 1.00 (t, 3H, J=7.33Hz), 1.49 (m, 2H), 1.84 (m, 2H), 2.77 (3 line m, 2H, J=7.7 Hz), 4.61 (s,2H), 7.68 (d, 1H, J=8.4 Hz), 7.80 (dd, 1H, J=8.4, 2.1 Hz), 8.27 (d, 1H,J=2.1 Hz), 11.02 (bs, 1H).

EXAMPLE 13 5-Bromomethyl-2-butylquinazolin-4(1H)-one

The product of Example 5 was treated as in Example 13 to give a 71%yield of a white solid. ¹ H-NMR (CDCl₃): 1.0 (t, 3H, J=7.3 Hz), 1.53,(m, 2H), 2.90 (m, 2H), 2.81 (3 line m, 2H, J=7.98 Hz), 5.31 (s, 2H),7.45 (m, 1H), 7.71 (m, 2H), 11.28 (bs, 1H).

EXAMPLE 14 6-Acetoxymethyl-2-butylquinazolin-4(1H)-one

To a solution of 2.1 g (7.0 mmol) of the quinazolinone prepared inExample 12 in 15 mL of dry DMF was added 1.74 g (20.0 mmol) of sodiumacetate. The mixture was heated to 60° C. for 3 hours. The reactionmixture was concentrated in vacuo and the residue dissolved in 100 mL ofCH₂ Cl₂. The solution was washed with water (3×20 mL), brine (1×20 mL)and dried over MgSO₄. The mixture was filtered and concentrated invacuo. The residue was recrystallized from MeOH/H₂ O to give 1.31 g (4.8mmol) of a colorless solid. 68% yield. ¹ H-NMR (CDCl₃): 0.99 (t, 3H,J=7.32 Hz), 1.50 m, 2H), 1.83 (m, 2H), 2.14 (t, 3H), 2.77 (3 line m, 2H,J=7.71 Hz), 5.23 (s, 2H), 7.69-7.78 (m, 2H), 8.25 (s, 1H), 10.90 (bs,2H).

EXAMPLE 15 5-Acetoxymethyl-2-butylquinazolin-4(1H)-one

The product of Example 13 was treated as in Example 14 to give afterrecrystallization from EtOAc a 77% yield of the desired acetylatedproduct.

¹ H-NMR (CDCl₃): 0.98 (t, 3H, J=7.38Hz), 1.50 (m, 2H), 1.88 (m, 2H),2.19 (s, 3H), 2.77 (3 line m, 2H, J=7.93 Hz), 5.85 (s, 2H), 7.48 (m,1H), 7.70 (m, 2H), 11.65 (bs, 1H).

EXAMPLE 16 6-Nitro-2-propylquinazolin-4(1H)-one

To a solution of 16.3 g (0.1 mol) of 2-amino-5-nitrobenzonitrile in 200ml of CH₂ Cl₂ at 0° C. was added 21 ml (0.15 mol) of triethyl aminefollowed by 0.3 g of DMAP and 11.71 g (0.11 mol) of butyryl chloride.The reaction mixture was warmed to room temperature and then heated overnight at 50° C. The solution was washed with 1N HCl (1×20 ml), water(1×20 ml), saturated NaHCO₃ (2×20 ml) and brine (1×20 ml) and dried overMgSO₄. The solution was filtered and concentrated in vacuo. The residuewas dissolved in 200 ml of MeOH to which was added 44 ml (0.22 mol) of5M NaOH solution followed by the dropwise addition of 25 ml (0.22 mol)30% H₂ O₂ and 50 ml of water. The mixture was refuxed for 4 hours,cooled and filtered. The filtrate was acidified with 1N HCl and theresulting precipitate recovered by filtration. The residue wasrecrystalized from MeOH to give 8.3 g (0.036 mol) of pale brown fluffycrystals. 36% yield.

¹ H-NMR (CDCl₃): 1.10 (t, 3H, J=7.4Hz), 1.93 (m, 2H), 2.79 (3 line m,2H, J=7.3Hz), 7.80 (d, 1H, J=8.9Hz), 8.55 (dd, 1H, J=2.5, 8.8Hz), 9.14(bs, 1H).

PREPARATION OF 5-Alkyl-2-aryl-2,4-dihydro-3H-1,2,4-triazol-3-onesEXAMPLE 17 2-(2-chlorophenyl)-5-Butyl-2,4-dihydro-3H-1,2,4-triazol-3-oneStep A: Preparation of ethyl valerimidate (Free Base)

A 12.7 g (76.7 mmol) sample of ethyl valerimidate hydrochloride(prepared from valeronitrile, ethanol, and hydrogen chloride gas asdescribed in A. J. Hill and I. Rabinowitz, J. Am. Chem. Soc., 1926, 48,734) was dissolved in 33% (w/w) potassium carbonate solution (made bydissolving 15 g of K₂ CO₃ in 30 mL of H₂ O) and immediately extractedwith either (3×40 mL). The combined ether layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give 7.09 g (72%) of theproduct as a clear oil, which was used directly in the next step.

¹ H NMR (300 MHz, CDCl₃, ppm): δ0.88 (t, J=7 Hz, 3H), 1.24 (t, J=7Hz,3H), 1.31 (m, 2H), 1.50 (m, 2H), 2.19 (t, J=7.5 Hz, 2H), 4.06 (q, J=7Hz, 2H), 6.84 (br s, 1H).

Step B: Preparation of ethyl N-carbethoxyvalerimidate

A solution of 6.5 g (50.3 mmol) of ethyl valerimidate (free base) in 90mL of dry CH₂ Cl₂ was treated with 7.71 mL (5.60 g, 55.3 mmol) oftriethylamine. The resulting solution was stirred under N₂ at -10° C. inan ice-salt bath as a solution of 4.81 mL (5.46 g, 50.3 mmol) of ethylchloroformate in 10 mL of CH₂ Cl₂ was added dropwise over 25 minutes.Upon completion of the addition, the cooling bath was removed, and themixture was stirred at room temperature for 2 hours. Next, the solventwas removed by evaporation in vacuo. The residue was taken up in hexaneand filtered to remove triethylamine hydrochloride. Concentration of thefiltrate yielded 7.08 g (70%) of the product as a yellow oil, suitablefor use in the next step without further purification. NMR indicated amixture of syn and anti isomers. TLC (98:2 CH₂ Cl₂ -MeOH) showed a closepair of spots, R_(f) 0.48, 0.52.

¹ H NMR (200 MHz, CDCl₃, ppm): δ0.86 (distorted t, J=7.5 Hz, 3H),2.15-2.35 (m, 8H), 2.4-2.65 (m, 2H), 2.19, 2.35 (t, J=7.5 Hz, 2H total),4.0-4.2 (m, 4H). EI-MS: m/e 201 (M⁺).

Step C: Preparation of5-butyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of 285 mg (2 mmol) of (2-chlorophenyl)hydrazine (generatedfrom the hydrochloride by partitioning between ether and 1N Na₂ CO₃) in3 mL of toluene was added 442 mg (2.2 mmol) of ethyl-carbethoxyvalerimidate (Example 4 Step B). The mixture was heated at45°-50° C. for 45 minutes. At this time the mixture was treated with 307mL (223 mg, 2.2 mmol) of triethylamine and then heated overnight at 95°C. The mixture was cooled and concentrated in vacuo. Flashchromatography of the residue on silica gel (gradient elution with0.6-2% methanol in CH₂ Cl₂) gave 257 mg (51%) of the product as anoff-white solid, mp 103°-104° C. homogeneous by TLC in 19:1 CH₂ Cl₂-MeOH.

¹ H NMR (200 MHz, CDCl₃, ppm): δ0.92 (t, J=7 Hz, 3H), 1.38 (m, 2H), 1.68(m, 2H), 2.57 (t, J=7.5 Hz, 2H), 7.3-7.55 (m, 4H), 12.04 (br s, 1H).

FAB-MS: m/e 252 (M+1).

Analysis for C₁₂ H₁₄ ClN₃ O

Calcd: C, 57.26; H, 5.61; N, 16.69.

Found: C, 57.31; H, 5.69; N, 16.58.

PREPARATION OF 5.6 DIALKYL PYRIMIDIN-4(3H)-ONE EXAMPLE 182-n-Butyl-5-ethyl-6-methylpyrimidin-4(3H)-one

A solution of 3.0 g valeramidine hydrochloride, 3.47 g ethyl2-ethylacetoacetate, and 5.8 mL triethylamine in 20 mL DMF was heated to120° C. for 18 hours. The mixture was diluted with brine and extractedthree times with ether. The combined organic material was washed withbrine, was dried over MgSO₄, was stripped of solvent in vacuo, and thenwas still flash chromatographed in 3% MeOH in CH₂ Cl₂ to give the titlecompound as a white solid.

¹ H NMR (300 MHz, CDCl₃) §2.62 (3 line n, 2H), 2.51 (4 line m, 2 H),2.32 (s, 3), 1.75 (m, 2H), 1.42 (6 line m, 2H), (1.10 (3 line m, 3H),0.95 (3 line m, 3H).

EXAMPLE 19 2-n-Butyl-5,6-dimethylpyrimidin-4(3H)-one

The title compound is prepared using the procedure in Example 18 andethyl 2-methylacetoacetate in place of ethyl 2-ethylacetoacetate.

PREPARATION OF 3-N-ALKYL-2-ALKYLQUINAZOLIN-4(3H)-ONE

A general procedure for the synthesis of3-N-alkylated-quinazolin-4(3H)-ones is given below.

A suspension of 1.1 mmol of NaH in 2 mL of dry DMF at 0° C. undernitrogen is treated with 1 mmol of the quinazolin-4(1H)-one as a solid(most quinazolin-4(1H)-ones prepared were insoluble in DMF). Immediateevolution of hydrogen could be observed as the quinazolin-4(1H)-one isdeprotonated and dissolves. After 30 minutes the solution was warmed toroom temperature for a further 30 minutes. To this solution cooled to 0°C. is added a solution of 1 mmol of the appropriatebromomethylphenyl/methanesulfonylmethylphenyl thiophene, benzothiopheneor furan, as prepared below, in 1.5 mL of DMF. After 30 minutes, thereaction mixture is warmed to room temperature and stirred overnight.The solution is concentrated in vacuo, and the residue dissolved in 50mL of EtOAc. The solution is washed with water (3×10 mL) and brine (2×10mL). The organic phase is dried over MgSO₄, filtered and concentrated invacuo. The residue is then chromatographed on a silica gel column.

The procedure herein described can be used to generate5-alkyl-2-aryl-3-N-alkyl-'2,4-dihydro-1,2,4-triazol-3-ones and2,5,6-trialkyl-3-N-alkylpyrimidin-4-(3H)-one. The general procedures forpreparing the methanesulfonylmethylphenyl bromomethylphenyl thiophenes,benzothiophenes and furans are described below using quinaolinones and2,4-dihydro-1,2,4-triazol-3-ones.

EXAMPLE 202-Butyl-6-methyl-3-[[4-[3-(1H-tetrazol-5-yl)-4-thienyl]phenyl]methyl]quinazolin-4(3H)-one(Compound 2 of Table VII) Step A: Preparation of3-bromo-4-(4-methylphenyl)thiophene (scheme II-1. compound 1a)

Through a solution of p-tolyltrimethyltin (3.17 g, 12.4 mmol) in drytoluene (8 mL) was bubbled N₂ for 5 min to degas the solution. To thiswas added 3,4-dibromothiophene (2.31 g, 9.56 mmol) and a catalyticamount of Pd(PPh₃)₄ (552 mg, 5 mol %). The reaction mixture was broughtto reflux (120° C.) and left overnight. The reaction was cooled to rtand the toluene was replaced by EtOAc. The insoluable salts were removedby filtration through a plug of celite. The product was purified byflash chromatography on a silica column eluting with hexane to afford1.09 g (45%) of the titled compound as a clear, colorless oil.

¹ H NMR (300 MHz, CDCl₃) δ2.39 (s, 3H), 7.21-7.26 (m, 4H), 7.33 (d, 1H),7.38 (d, 1H); FAB mass spectrum, m/e 252/254 (m+, calcd for C₁₁ H₉ SBr,253).

Step B: Preparation of 3-cyano-4-(4-methylphenyl)thiophene (scheme II-1,compound 1b)

To a solution of the product of Step A (329 mg, 1.30 mmol) in quinoline(3 mL) was added CuCN (233 mg, 2.60 mmol) and the solution heated toreflux (235° C.) overnight. The reaction was cooled and Et₂ O was added.The solution was washed with 9N HCl and brine, dried over anhydrousMgSO₄, and filtered. The product was purified by flash chromatography ona silica column using Hex/EtOAc (35:1) to afford 174 mg (67%) of thetitled compound as a light yellow solid.

¹ H NMR (200 MHz, (CDCl₃) δ2.42 (s, 3H), 7.28 (d, 2H), 7.36 (d, 1H),7.53 (d, 2H), 8.04 (d, 1H); FAB mass spectrum, m/e 199 (m+, calcd forC₁₂ H₉ SN, 199).

Step C: Preparation of3-N-triphenylmethyltetrazolyl-4-(4-methylphenyl)thiophene (scheme II-1.compound 1c)

To a solution of the product of Step B (174 mg, 0.873 mmol) in drytoluene (7 ml) was added Me₃ SnN₃ (1.07 g, 5.22 mmol) and the solutionbrought to reflux (130° C.). A white solid that is product precipitates.The reaction was left overnight. There was still starting materialpresent and another 363 mg of Me₃ SnN₃ was added. After an additional 5hours the reaction was cooled to RT. To the reaction was added CH₂ Cl₂and the reaction was washed with 2N HCl and water, dried over MgSO₄ andfiltered. The volume was reduced and NEt₃ (244 μl, 1.75 mmol) and Ph₃CCl (219 mg, 0.787 mmol) were added. After 2 hours Et₂ O/EtOAc was addedto the reaction and the solution was washed with 10% citric acid, 1NNaOH and water, dried over MgSO₄ and filtered. The titled compound wasisolated in 94% yield, Rf=0.33 (10:1 hex/EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ2.31 (s, 3H), 6.95 (d, 8H), 7.09 (d, 2H),7.21-7.34 (m, 10H), 8.00 (d, 1H); FAB mass spectrum, m/e 485 (m+1, calcdfor C₃₁ H₂₄ SN₄, 485).

Step D: Preparation of3-N-triphenylmethyltetrazolyl-4-(4-bromomethylphenyl)thiophene (schemeII-1. compound 1e, R=H)

To a solution of the product of Step C (329 mg, 0.680 mmol) in dry CCl₄(3 mL) was added NBS (133 mg, 0.749 mmol) and a catalytic amount ofAIBN. The mixture was heated to reflux (100° C.). After 2 h the reactionwas cooled to rt and the insoluable succinimide removed by filtration.The solvent was replaced by EtOAc and washed with 1N NaOH and brine,dried over MgSO₄ and filtered. The solvent was removed to afford 428 mg(100%) of the crude product as a yellow foam. Rf=0.32 (10:1/Hex:EtOAc).

Step E: Preparation of2-butyl-6-methyl-3-[[4-[3-(N-triphenylmethyltetrazole)-4-thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Scheme II-8, compound 8b)

To a solution of 2-butyl-6-methylquinazolinone (105 mg, 0.487 mmol) indry DMF (2 mL) under N₂ was added NaH (25.3 mg, 0.843 mmol). Thereaction was allowed to stir for 30 min. To this was added a solution ofthe product of Step D (0.340 mmol, crude) in dry DMF (1 mL). After 5 hthe reaction was quenched with sat'd NH₄ Cl solution. The DMF wasreplaced with CH₂ Cl₂ and the mixture filtered. The product was purifiedby flash chromatography on a silica column using a gradient of Hex/EtOAc(15:1-7) to yield 74.0 mg (29% 2 steps) of the major product, Rf=0.33(3:1 Hex/EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H), 1.31-1.38 (sextet, 2H),1.68-1.73 (quintet, 2H), 2.48 (s, 3H), 2.65 (t, 2H), 5.33 (s, 2H),6.90-7.28 (m, 24H), 7.57 (s, 2H), 8.02 (dd, 1H), 8.10 (s, 1H).

Step F: Preparation of2-butyl-6-methyl-3-[[-[3-(1H-tetrazol-5-yl)-4-thienyl]phenyl]methyl]quinazolin-4-(3H)-one.(Compound 2 of Table VII)

To a solution of the product of Step E (74.0 mg, 0.106 mmol) in methanol(3 mL) was added 9N HCl (10 drops). Within 30 min the reaction wascompleted. The methanol was removed and the product triturated with Et₂O to yield 45.9 mg (88%) of the titled product, Rf=0.73 (50:10:1 CHCl₃/MeOH/HOAc). FAB mass spectrum, m/e 457 (M+1, calcd for C₂₅ H₂₄ SON₆457).

¹ H NMR (300 MHz, CD₃ OD) δ0.97 (t, 3H), 1.48-1.70 (sextet, 2H),1.71-1.75 (quintet, 2H), 2.61 (s, 3H), 3.15 (t, 2H), 5.61 (s, 2H),7.28-7.46 (m, 4H), 7.68 (d, 1H), 7.73 (d, 1H), 7.95 (dd, 1H), 8.09 (d,1H), 8.23 (s, 1H).

EXAMPLE 212-Butyl-6-methyl-3-[[4-[2-bromo-3-[1H-tetrazol-5-yl)-4-thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 17 of Table VII) Step A: Preparation of2-bromo-3-(N-triphenylmethyltetrazol-5-yl)-4-(4-methylphenyl)thiophene(scheme II-1, compound 1d R=Br)

To a solution of the product of Example 20 Step C (101 mg, 0.208 mmol)in dry THF (2 ml) cooled to -78° C. with a dry ice/acetone bath under N₂was added a 1.7M tBuLi solution (0.190 ml, 0.323 mmol). The reactionturned slowly from orange to red then the color dissipated. Another0.190 ml of tBuLi was added to the reaction. As soon as the red colorpersisted Br₂ (0.40 ml, 0.42 mmol) was added. The product was purifiedby flash chromatography on a silica column using Hex/EtOAc (35:1).Removal of the solvent afforded 60 mg (51%) of the crude titled product.Rf=0.48 (10:1 Hex/EtOAc).

Step B: Preparation of2-bromo-3-N-triphenylmethyltetrazol-5-yl-4-(4-bromomethylphenyl)thiophene(scheme II-1, compound 1e, R=Br)

To a solution of the product of Step A (22 mg crude) in dry CCl₄ (3 mL)was added NBS (7 mg, 0.0448 mmol) and a catalytic amount of AIBN. Thereaction was brought to reflux (100° C.). After 2 h the reaction wascooled to rt and the insoluable succinimide was removed by filtration.The solvent was replaced by Et₂ O/EtOAc and washed with 1N NaOH andbrine, dried over MgSO₄ and filtered. Removal of the solvent afforded 43mg (100%) of the crude titled compound. Rf=0.66 (3:1/Hex:EtOAc).

Step C & D: Alkylation and deprotection, following the procedure of e.g.20, Steps E through F, provides the titled compound.

EXAMPLE 222-Butyl-6-methyl-3-[[4-[2-(1H-tetrazol-5yl)-3-thienyl]phenyl]methyl]quinazolin-4(3H)-one(Compound 14 of Table VII) Step A: Preparation of2-[(N-triphenylmethyltetrazol-5-yl]thiophene (scheme II-3, compound 3a,Y=S)

To a solution of 2-cyanothiophene (1.4 g; 12.8 mmol) in dry toluene (10ml) was added Me₃ SnN₃ (2.8 g; 13.65 mmol). The mixture was stirred atreflux under N₂ for 12 hours. The reaction was cooled to roomtemperature diluted with CH₂ Cl₂ and washed with 2N HCl soln and H₂ O.The organic was dried over anhydrous MgSO₄ and concentrated in vacuo.The residue, containing the free tetrazole, was dissolved in CH₂ Cl₂ (10mL) and Ph₃ CCl (3.2 g; 0.9 equiv.) and NEt₃ (3.6 mL) were added. After20 minutes the mixture was diluted with Et₂ O/EtOAc and washed with 1NNaOH, 10% citric acid and brine. The organic was dried over anhydrousMgSO₄ and concentrated in vacuo. The product was purified byrecrystallization from hexanes. The titled compound was isolated in 80%yield, Rf=0.33 (10:1 hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃), δ7.12-7.21 (comp, 8H), 7.28-7.40 (comp, 8H),7.42 (dd, 1H), 7.79 (dd, 1H).

Step B: Preparation of2-trimethylsilyl-5-(N-triphenylmethyltetrazol-5-yl)thiophene (schemeII-3, compound 3b, Y=S)

A solution of the product of Step A (1.00 g, 2.54 mmol) in dry THF (10ml) under N₂ was cooled to -20° C. with a dry ice/acetone bath. To thiswas added 1.6M nBuLi solution (2.38 ml, 3.81 mmol) by syringe. Thereaction mixture turned orange then red and cloudy. The reaction waswarmed to -10° C. and stirred for 45 min. The reaction was then cooledto -50° C. and TMSCl (0.322 mL, 2.54 mmol) was added by syringe. Thereaction was warmed to 0° C. and quenched with sat'd NH₄ Cl solution (5drops). The solvent was replaced by Et₂ O/EtOAc and washed with waterand brine, dried over MgSO₄ and filtered. The product was purified byflash chromatography on a silica column eluting with Hex/EtOAc (40:1).Removal of the solvent affored 849 mg (72%) of the titled product as aslightly orange solid. Rf=0.40 (15:1/Hex:EtOAc).

¹ H NMR (400 MHz, CDCl₃) δ0.32 (s, 9H), 7.13-7.15 (m, 5H), 7.22 (d, 1H),7.31-7.33 (m, 10H), 7.82 (d, 1H).

Step C: Preparation of2-trimethylsilyl-4-trimethyltin-5-(N-triphenylmethyltetrazol-5-yl)thiophene(scheme II-3l, compound 3c, Y=S).

A solution of the product of Step B (752 mg, 1.61 mmol) in dry THF (6mL) under N₂ was cooled to -20° C. with a dry ice/acetone bath. To thiswas added a 1.6M nBuLi solution (1.53 ml, 2.45 mmol) by syringe. Thereaction turned red. As the reaction was warmed to -10° C., the colorbegan to return to orange indicating quenching. The reaction was cooledagain to -20° C. and another 1.53 ml of the nBuLi solution was added.The solution turned dark red. The reaction was warmed to -10° C. andallowed to stir at this temperature for 45 min. The reaction was cooledto -60° C. and a solution of Me₃ SnCl (844 mg, 4.24 mmol) in dry THF (2ml) was added by cannula.

The reaction was warmed to rt and quenched with sat'd NH₄ Cl solution.To the flask was added Et₂ O/EtOAc and the solution washed with 1N NaOHand brine, dried over MgSO₄ and filtered. The product was purified byflash chromatography on a silica column eluting with Hex/EtOAc (50:1).Removal of the solvent affored 879 mg (87%) of the titled compound as awhite solid. Rf=0.54 (10:1/Hex:EtOAc).

¹ H NMR (200 MHz, CDCl₃) δ0.13 (s, 9H), 0.35 (s, 9H,) 7.12-7.35 (m,16H).

Step D: Preparation of2-trimethylsilyl-4-(4-(1-methoxycarbonyl)phenyl)-5-(N-triphenylmethyltetrazol-5-yl)thiophene(scheme II-3, compound 3d, Y=S)

To a concentrated solution of the product of Step C (194 mg, 0.308 mmol)in dry DMF (1.5 ml) was added p-iodomethylbenzoate (153 mg, 0.583 mmol)and Pd(PPh₃)₂ Cl₂ (22 mg, 10 mol %). The reaction was heated at 75° C.for several hrs. Because some trityl had been removed by the heat, NEt₃(0.0645 mL, 0.463 mmol) and Ph₃ CCl (59 mg, 0.21 mmol) were added. TheDMF was replaced by EtOAc and the product was purified by flashchromatography on a silica column eluting with Hex/EtOAc (15:1). Removalof the solvent afforded 116 mg of the titled compound as a white solid.Rf=0.32 (10:1/Hex:EtOAc).

Step E: Preparation of mesylate 3e (scheme II-3, compound 3e, Y=S)

To a solution of the product of step D (116 mg crude) in dry THF (2 ml)under N₂ and cooled to 0° C. was added an LAH solution (0.580 ml, 0.580mmol) by syringe. When the gas evolution subsided, about 5 min, the icebath was removed and the reaction warmed to RT. To the reaction wasadded Et₂ O then 1 drop water, 1 drop 5.0N NaOH, and 1 drop water. Theinsoluable salts precipitated. MgSO₄ was added and the solids wereremoved by filtration. Removal of the solvent afforded 142 mg (100% 2steps) of the crude primary alcohol. Rf=0.41 (2:1/Hex: EtOAc). Theprimary alcohol (142 mg crude) was dissolved in dry CH₂ Cl₂ (1.5 mL)under N₂ and was cooled to 0° C. To this solution was added NEt₃ (0.0595mL, 0.429 mmol), CH₃ SO₂ Cl (0.030 mL, 0.388 mmol), and a catalyticamount of 4-dimethylaminopyridine (2 mg, 9 mol %). The reaction was keptat 0° C. After an hour the reaction was warmed to rt and Et₂ O/EtOAc wasadded to the reaction. The solution was washed with 10% citric acid, 1NNaOH and brine, dried over MgSO₄, and filtered. Removal of the solventafforded 113 mg (90% for steps D through E) of the crude titledcompound. Rf=0.42 (2:1/Hex: EtOAc). The mesylate was used crude withoutfurther purification.

Steps F and G: Alkylation with the product of example 19, Step E,following the procedure of Example 17, Steps E through F provides thetitled compound EXAMPLE 232-Butyl-6-methyl-3-[[4-[2-(1H-tetrazol-5yl)-3-furanyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 27 of Table VII) Step A: Preparation of2-[(N-triphenylmethyl)tetrazol-5-yl]furan (scheme II-3, compound 3a,Y=O)

To a solution of 2-cyanofuran (3.84 g; 41.3 mmol) in dry toluene (30 mL)was added Me₃ SnN₃ (10 g; 1.2 equiv.). The mixture was stirred at refluxunder N₂ for 12 hours. The reaction mixture was diluted with CH₂ Cl₂ andwashed with 2N HCl soln and H₂ O. The organic was dried over anhydrousMgSO₄ and concentrated in vacuo. The residue was dissolved in CH₂ Cl₂(20 mL) and NEt₃ (11.0 mL; 2 equiv.) and Ph₃ CCl (10.3 g; 0.9 equiv.)were added. After 1 hour the mixture was diluted with Et₂ O/EtOAc andwashed with 10% citric acid, 1N NaOH and brine. The organic was driedover MgSO₄ and concentrated in vacuo. The product was crystallized fromhexanes. The title compound was isolated in 35% yield, Rf=0.30 (10:1hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) δ6.53 (dd, 1H), 7.08-7.18 (comp, 6H), 7.21-7.40(comp, 10H), 7.57 (dd, 1H).

Step B: Preparation of2-trimethylsilyl-5-(N-triphenylmethyltetrazol-5-yl)furan (scheme II-3,compound 3b, Y=O)

A solution of the product of Step A (1.00 g, 2.65 mmol) in dry THF (10mL) under N₂ was cooled to -20° C. with a dry ice/acetone bath. To thiswas added 1.6M n BuLi solution (2.5 mL, 4.0 mmol). The reaction slowlyturned red in color. As the reaction was warmed to -10° C., the colorchanged to brown and the reaction became cloudy. The reaction was cooledto -50° C. and TMSCl (0.335 mL, 2.64 mmol) was added by syringe. Thereaction was warmed to 0° C. and quenched with sat'd NH₄ Cl solution (6drops). The solvent was replaced by EtOAc and washed with brine, driedover MgSO₄ and filtered. The product was purified by flashchromatography on a silica column eluting with Hex/EtOAc (40:1). Removalof the solvent affored 590 mg (50%) of the titled product as a whitesolid. Rf=0.32 (15:1/Hex:EtOAc).

¹ H NMR (400 MHz, CDCl₃) δ0.29 (s, 9H), 6.69 (d, 1H), 7.04 (d, 1H),7.12-7.35 (m, 15H).

Step C: Preparation of2-trimethylsilyl-4-trimethyltin-5-(N-triphenylmethyltetrazol-5-yl)furan(scheme II-3, compound 3c, Y=O)

A solution of the product of Step B (532 mg, 1.18 mmol) in dry THF (5mL) under N₂ was cooled to -20° C. with a dry ice/acetone bath. To thiswas added 1.6M nBuLi solution (1.13 mL, 1.81 mmol) by syringe. A lightred color developed. The reaction was warmed to -10° C. and allowed tostir at this temperature for 45 min. Because the color faded another1.13 ml of 1.6M nBuLi was added. The reaction was cooled to -60° C. anda solution of Me₃ SnCl (500 mg, 2.5 mmol) in dry THF (1.5 mL) was addedby cannula. The reaction was warmed to rt. To the flask was added Et₂O/EtOAc and the solution washed with 1N NaOH, water, and brine, driedover MgSO₄ and filtered. The product was purified by flashchromatography on a silica column eluting with Hex/EtOAc (50:1). Rf=0.54(10:1/Hex:EtOAc). Removal of the solvent affored 520 mg (72%) of thetitled compound as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ0.05 (s, 9H), 0.30 (s, 9H), 6.68 (s, 1H),7.10-7.13 (m, 5H), 7.30-7.32 (m, 10H).

Step D: Preparation of2-trimethylsilyl-4-(4-(1-methoxycarbonyl)phenyl)-5-(N-triphenylmethyltetrazol-5-yl)furan(scheme II-3, compound 3d, Y=O)

To a concentrated solution of the product of Step C (187 mg, 0.305 mmol)in dry DMF (1.5 mL) was added p-iodomethylbenzoate (160 mg, 0.612 mmol)and Pd(PPh₃)₂ Cl₂ (22 mg, 10 mol %). The reaction was heated at 75° C.for several hrs. Because some trityl had been removed by the heat, NEt₃(0.043 mL, 0.31 mmol) and Ph₃ CCl (41 mg, 0.15 mmol) were added. The DMFwas replaced by EtOAc and the product was purified by flashchromatography on a silica column eluting with a gradient of Hex/EtOAc(30:1-15:1). Removal of the solvent affored 100 mg (56%) of the titledcompound. Rf=0.23 (10:1/Hex:EtOAc).

¹ H NMR (400 MHz, CDCl₃) δ0.34 (s, 9H), 3.93 (s, 3H), 6.86 (s, 1H),7.05-7.07 (m, 6H), 7.24-7.34 (m, 9H), 7.54 (d, 2H), 7.86 (d, 2H).

Step E: Preparation of3-(4-(1-methanesulfonyloxymethyl)phenyl)-2-(N-triphenylmethyltetrazol-5-yl)furan(scheme II-3, compound 3e, Y=O)

To a solution of the product of Step D (100 mg, 0.172 mmol) in dry THF(2 mL) under N₂ and cooled to 0° C. was added an 1.0M LAH solution(0.520 mL, 0.520 mmol) by syringe. When the gas evolution subsided theice bath was removed and the reaction warmed to rt. To the reaction wasadded Et₂ O then 1 drop water, 1 drop 5.0N NaOH, and 1 drop water. Theinsoluable salts precipitated and MgSO₄ was added and the solids removedby filtration. The solvent was removed in vacuo and the crude alcohol,Rf=0.35 (2:1/Hex:EtOAc), was used in the next step without furtherpurification. A solution of the primary alcohol in dry CH₂ Cl₂ (1.5 mL)under N₂ was cooled to 0° C. To this solution was added NEt₃ (0.0527 mL,0.378 mmol), CH₃ SO₂ Cl (0.0266 mL, 0.344 mmol), and a catalytic amountof 4-dimethylaminopyridine (3 mg, 15 mol %). The reaction was kept at 0°C. After an hour the reaction was warmed to rt and Et₂ O/EtOAc was addedto the reaction. The solution was washed with 10% citric acid, 1N NaOHand brine, dried over MgSO₄, and filtered. Removal of the solventafforded 105 mg (96% 2 steps) of the crude titled compound as a brightyellow solid. Rf=0.43 (2:1/Hex:EtOAc). The mesylate was used crudewithout further purification.

Steps F & G: The titled compound was completed by alkylation followed bydeprotection, following the procedures of Example 20, Steps E through FEXAMPLE 242-Butyl-6-methyl-3-[[4-[2-(N-benzoylsulfonamido)-3-benzothienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 38 of Table VII) Step A: Preparation of3-(4-methylphenyl)benzothiophene (scheme II-4, compound 4a, Y=S, whereR¹¹ and R¹² are joined to form a phenyl ring)

To a solution of 3-bromobenzothiophene (709 mg, 3.33 mmol) andp-tolytrimethyltin (850 mg, 1.0 equiv) in dry toluene (12 mL) under N₂was added Pd(PPh₃)₄ (192 mg, 5 mol %). The mixture was strirred atreflux for 12 h. The solvent was removed in vacuo and the residue waspartially dissolved in hex/EtOAc (10:1) and filtered through a plug ofsilica. The solvent was removed to afford 658 mg (88%) of crude titledcompound. Rf=0.56 (25:1 hex/EtOAc).

Step B: Preparation of 3-(4-methylphenyl)-2-chlorosulfonylbenzothiophene(scheme II-4, compound 4c, Y=S, where R¹¹ and R¹² are joined to form aphenyl ring

To a solution of the product of Step A (293 mg, 1.308 mmol) in dry THF(5 mL) cooled to -20° C. under N₂ was added 1.6M nBuLi (2.44 mL, 3.0equiv). The reddish-brown anion was stirred at -20° C. for 50 min thencooled to -70° C. and SO₂ (g) was bubbled in until the anion colordisappeared (ca. 5 min). To the now slightly yellow solution was addedN-chlorosuccinamide (350 mg, 2 equiv) and the mixture was stirred for 1h and warmed to rt by removing the ice bath. The reaction mixture wasdiluted with Et₂ O/EtOAc and washed with H₂ O, 5% NaHO₃ soln, and brine.The organic was dried over anhydrous MgSO₄ and concentrated in vacuo toafford crude titled compound. Rf=0.45 (25:1 hex/EtOAc).

Step C: Preparation of3-(4-methylphenyl)-2-(N-t-butylsulfonamido)benzothiophene (scheme II-4,compound 4d, Y=S, where R¹¹ and R¹² are joined to form a phenyl ring)

To a solution of the entire crude product of Step B in dry CH₂ Cl₂ (5mL) was added tbutylamine (2 mL). The mixture was stirred for 2 days andthen diluted with CH₂ Cl₂ and washed with 1N HCl, H₂ O and brine. Theorganic was dried over anhydrous MgSO₄ and concentrated in vacuo. Theproduct was purified by flash chromatography by first eluting withhex/EtOAc (6:1) and then with CH₂ Cl₂ to afford 115 mg (25% for step Band C) of the tiltled compound. Rf=0.23 (6:1 hex/EtOAc).

¹ H NMR (400 MHz, CDCl₃) δ1.04 (s, 9H), 2.44 (s, 3H), 4.01 (s, 1H), 7.33(d, 2H), 7.36 (m, 1H), 7.43-7.48 (comp m, 3H), 7.55 (dd, 1H), 7.87 (ddd,1H); FAB mass spectrum, m/e 360 (m+H, calcd for C₁₉ H₂₁ NO₂ S₂, 360).

Step D: Preparation of3-(4-bromomethylphenyl)-2-(N-t-butylsulfonamido)benzothiophene (scheme(II-4, compound 4e, Y=S, where R¹¹ and R¹² are joined to form a phenylring)

To a solution of the product of Step C (115 mg, 0.3203 mmol) in drybenzene (5 mL) was added a catalytic amount of AIBN andN-bromosuccinamide (68 mg, 1.2 equiv). The mixture was stirred at refluxunder N₂ for 3 h. After cooling to rt the reaction mixture was dilutedwith Et₂ O/EtOAc and washed with H₂ O and brine. The organic was driedover anhydrous MgSO₄ and concentrated in vacuo to afford 147 mg (100%)of the titled compound. Rf=0.18 (6:1 hex/EtOAc). The bromomethylcompound was used crude without further purification.

Step E: Preparation of2-butyl-6-methyl-3-[[4-[2-(N-t-butylsulfonamido)-3-benzothienyl]phenyl]methyl]quinazolin-4-(3H)-one(scheme II-10, compound 10a)

To a solution of 2-butyl-6-methylquinazolin-4-(3H)-one from Example 1 indry DMF was added 80% NaH in oil (1.5 equiv). When H₂ evolution ceased asolution of the product of Step D in DMF was added. The mixture wasstirred at rt for 3 h then quenched with satd NH₄ Cl soln andconcentrated in vacuo. The residue was dissolved in CH₂ Cl₂ dried overanhydrous MgSO₄, filtered and concentrated in vacuo. A small sample ofthe reaction mixture was purified by flash chromatography eluting withhex/EtOAc to provide the titled compound in pure form.

Step F: Preparation of2-butyl-6-methyl-3-[[4-[2-(sulfonamido)-3-benzothienyl]phenyl]methyl]quinazolin-4-(3H)-one(scheme II-10, compound 10b)

A solution of the entire product of Step E in TFA and anisole (2 drops)was stirred for 24 h. The TFA was removed at high vacuum and crudesulfonamide remained.

Step G: Preparation of2-butyl-6-methyl-3-[[4-[2-(N-benzoylsulfonamido)-3-benzothienyl]phenyl]methyl]quinazolin-4-(3H)-one(scheme II-10, compound 10c)

To a solution of the product of Step F in dry pyridine was added acatalytic amount of DMAP and benzoyl chloride (10 equiv). After stirringfor 3 h the pyridine was removed at high vacuum and the residue wastaken up in CH₂ Cl₂ and washed with 5% citric acid soln and H₂ O. Theorganic was dried over anhydrous MgSO₄ and concentrated in vacuo. Theproduct was purified by flash chromatography.

EXAMPLE 252-Butyl-6-methyl-3-[[4-[2-(N-benzoylsulfonamido)-3thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 12 of Table VII) and2-Butyl-6-methyl-3-[[4-[5-trimethylsilyl-2-(N-benzoylsulfonamido)-3-thienyl]methyl]quinazolin-4-(3H)-oneStep A: Preparation of3-bromo-2-t-butylsulfonamido-5-trimethylsilylthiophene. (scheme II-5,compound 5a, Y=S)

Part 1: To a solution of 2-thiophenesulfonyl chloride (1.22 g, 6.70mmol) in dry CH₂ Cl₂ (25 mL) at rt was added tBuNH₂ (1.55 mL, 2.2equiv). After stirring at rt overnight the mixture was diluted withether and washed with 1N HCl, a sat'd solution of NaHCO₃ and brine. Theorganic was dried over anhydrous MgSO₄ and concentrated in vacuo toprovide 1.42 g (97%) of t-butylsulfonamido-2-thiophene, Rf=0.50 (2:1hex/EtOAc).

Part 2: To a solution of t-butylsulfonamido-2-thiophene (500 mg, 2.28mmol) in dry THF (5 mL) cooled to 0° C. under a nitrogen atmosphere wasadded 1.6M nBuLi (4 mL, 6.4 mmol). After stirring for 30 mintrimethylsilylchloride (0.64 mL, 2.2 equiv) was added via syringe. Themixture was stirred for 10 min then 1.6M nBuLi (1.5 mL, 2.4 mmol) wasadded. After stirring for 30 min Br₂ ((0.26 mL, 1.19 equiv) was added.The mixture was allowed to warm to rt and diluted with ether and washedwith 1N NaOH and brine. The organic was dried over anhydrous MgSO₄ andconcentrated in vacuo. The product was purified by flash chromatographyeluting with hex/EtOAc (8:1) to afford 198 mg (26%) of the titledcompound, Rf=0.32 (6:1 hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) d 0.33 (s, 9H), 1.27 (s, 3H), 5.01 (bs, 1H),7.11 (s, 1H).

Step B: Preparation of3-p-tolyl-2-t-butylsulfonamido-5-trimethylsilylthiphene. (scheme II-5,compound 5b, Y=S)

To a solution of the product of Step A (176 mg, 0.536 mmol) andp-tolyltrimethyltin (205 mg, 1.5 equiv) in dry DMF (0.8 mL) undernitrogen was added PdCl₂ (PPh₃)₂ (38 mg, 10 mol %). The mixture wasstirred under nitrogen at 80° C. for 6 h. The DMF was removed at highvacuum and the residue was partially dissolved in EtOAc and filtered.The filtrate was concentrated in vacuo and the product was purified byflash chromatography eluting with hex/EtOAc (17.5:1) to afford 116 mg(62%) of the titled compound, Rf=0.31 (10:1 hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) d 0.35 (s, 9H), 0.98 (s, 9H), 2.39 (s, 3H),4.11 (bs, 1H), 7.12 (s, 1H), 7.26 (d, 2H), 7.50 (d, 2H).

Step C: Preparation of3-(4-Bromomethylphenyl)-2-t-butylsulfonamido-5-trimethylsilylthiophene.(scheme II-5, compound 5c, Y=S)

To a solution of the product of Step B (207 mg, 0.542 mmol) in dry CCl₄(3 ml), heated to dissolve the reagent, was added NBS (116 mg, 0.651mmol) and a catalytic amount of AIBN. The reaction was refluxed (110°C.) for 3 h then cooled to rt and the insoluable succinimide was removedby filtration. The solvent was diluted with Et₂ O/EtOAc and washed withwater (2×) and brine, dried over MgSO₄ and filtered. The solvent wasremoved and the crude titled product product (250 mg) dried thoroughlyovernight.

Step D: Preparation of2-Butyl-6-methyl-3-[[4-[2-(N-tbutylsulfonamido)-3-thienyl]phenyl]methyl]quinazolin-4(3H)-one[compound 9b, (scheme II-9) where X¹ --X² --X³ --X⁴ =--CH--CH--S--CZ--and Z=SO₂ NHtBu] and2-butyl-6-methyl-3-[[4-[5-trimethylsilyl-2-(N-butylsulfonamido)-3-thienyl]phenyl]methyl]quinazolin-4(3H)-one[compound 9a, (scheme II-9) where X¹ --X² --X³ --X⁴=--CH--C(TMS)--S--CZ-- and Z=SO₂ NHtBu]

To a solution of 2-butyl-6-methylquinazolin-4(1)-one, the product ofExample 1, in dry DMF under N₂ is added NaH. The reaction is allowed tostir for 30 min. To this is added a solutio nfo the product of step C indry DMF. After 3 h th ereaction was quenched with sat'd NH₄ Cl solution.The DMF was replaced with EtOAc, dried over MgSO₄ and the insoluablesalts removed by filtration. The products were purified by flashchromatography on a silica column isolating two products: one where X¹--X² --X³ --X⁴ =--CH--C(TMS)--S--CZ-- and Z=SO₂ NHtBu and the otherwhere X¹ --X² --X³ --X⁴ =--CH--CH--S--CZ-- and =SO₂ NHtBu.

Step E: Preparation of2-butyl-6-methyl-3-[[4-[2-(N-benzoylsulfonamido)-3-thienyl]phenyl]methyl]quinazolin-4(3H)-one(Compound 12 of Table VII) [compound 9b, (scheme II-9) where X¹ --X²--X³ --X⁴ =--CH--CH--S--CZ-- and Z=SO₂ NHCOPh] and2-butyl-6-methyl-3-[[4-[5-trimethylsilyl-2-(N-benzoylsulfonamido)-3-thienyl]methyl]quinazolin-4(3H)-one[compound 9a, (scheme II-9) where X¹ --X² --X³ --X⁴=--CH--C(TMS--S--CZ-- and Z=SO₂ NHCOPh]

Part 1: To the dry product (containing a the TMS group) of Step D wasadded a catalytic amount of anisole and TFA (2 ml) and the reaction isallowed to stir overnight. The next day when the TFA was removed thereaction became a deep red color. The two products, with and without theTMS group present, were free based by eluting through silica columnusing CHCl₃ /MeOH/NH₄ OH eluant. The two products can be difficult toseparate. The mixture can be used in the following step.

Part 2: To the mixture obtained in part 1 (crude) in dry pyridine isadded benzoylchloride and a catalytic amount of DMAP.

After about 2 h the sides of the flask can be rinsed with additionalpyridine and the reaction is allowed to stir another 30 min. Thereaction is concentrated then diluted with CH₂ Cl₂ and washed with 10%citric acid (2×) and water, dried over MgSO₄, filtered and the solventremoved. The products can be purified by flash chromatography on asilica column or HPLC.

EXAMPLE 262-Butyl-6-methyl-3-[[4-[3-(N-benzoylsulfonamido)-2-thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 11 of Table VII) [compound 9b, scheme II-9, where X¹ --X² --X³X⁴ =--S--CH--CH--CZ-- and Z=SO₂ NHCOPh] Step A: Preparation of2,5-dibromo-3-t-butylsulfonamidothiophene (scheme II-7, compound 7b,Y=S)

To chlorosulfonic acid (4.5 mL) was added 2,5-dibromothiophene (0.505 g,2.09 mmol) by syringe. On mixing the reaction turned dark orange-brown.After 10 min the reaction was poured very carefully over ice (100 ml).The solution turned bright yellow. The product was extracted from thewater layer using EtOAc/Et₂ O (3×). The combined organic layers werewashed with water and brine, dried over MgSO₄ and filtered. The solventwas replaced with dry CH₂ Cl₂ (4.5 ml) and t-butylamine (0.659 mL, 6.27mmol) was added. The reaction was stirred overnight. The next day thereaction was diluted with more CH₂ Cl₂ and washed with 1N HCl (3×),dried over MgSO₄ and filtered. The product was purified by flashchromatography on a silica column eluting with Hex/EtOAc (20:1) toafford 470 mg (60%) of the titled compound, Rf=0.16 (10:1Hex/EtOAc).

¹ H NMR (400 MHz, CDCl₃) δ1.25 (s, 9H), 4.75 (s, 1H), 7.30 (s, 1H).

FAB mass spectrum, m/e 378 (M+1, calcd for C₄ H₁₁ S₂ O₂ NBr₂ ; 378).

Step B: Preparation of 3-t-butylsulfonamidothiophene (scheme II-7,compound 7c, Y=S)

To a solution of the product of Step A (1.70 g, 4.52 mmol) in 24% byvolume glacial acetic acid/water (5 mL) was added Zn dust (1.73 g, 26.6mmol). The mixture was refluxed (120° C.) overnight. The next day thereaction was cooled, diluted with EtOAc and filtered. Et₂ O/EtOAc wasadded and the solution washed with 6N HCl (3×), water, carefully with 5%NaHCO₃ (2×) and brine. The solution was dried over MgSO₄ and filtered.The solvent was removed to afford 851 mg (86%) of the titled compound,Rf=0.23 (10:1 Hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) δ1.25 (s, 9H), 4.42 (s, 1H), 7.31-7.40 (m, 2H),7.92-7.95 (dd, 1H).

Step C: Preparation of 2-bromo-3-t-butylsulfonamidothiophene (schemeII-7, compound 7d, Y=S)

To a solution of the product of Step B (230 mg, 1.05 mmol) in dry THF (5mL) cooled to -78° C. in a dry ice/acetone bath under N₂ was added 1.6Mn-butyllithium (3.28 ml, 5.25 mmol) dropwise. The reaction was warmed to-50° C. then cooled back to -78° C. and Br₂ (269 ml, 5.24 mmol) wasadded. The bath was removed and the reaction was warmed to rt. Thereaction was quenched with sat'd NH₄ Cl solution. The solvent wasreplaced with Et₂ O/EtOAc and the reaction solution washed with water,1N NaOH, and brine. The solution was dried over MgSO₄, filtered and thesolvent removed to afford 298 mg (95%) of the titled compound, Rf=0.53(2:1 Hex/EtOAc).

¹ H NMR (400 MHz, CDCl₃) δ1.22 (s, 9H), 4.89 (s, 1H), 7.24 (d, 1H), 7.31(d, 1H).

Step D: Preparation of 2-p-tolyl-3-t-butylsulfonamidothiophene (schemeII-7, compound 7e, Y=S)

To solution of the product of Step C (4.59 mmol, crude) in dry DMF (1mL) was added p-tolyltrimethyltin (1.77 g, 6.95 mmol) and a catalyticamount of Pd(PPh₃)₂ Cl₂ (325 mg, 0.463 mmol). The reaction was heated at75°-80° C. for 5 h. The reaction was cooled to rt and the solventreplaced with EtOAc and filtered. The product was purified by flashchromatography on a silica column eluting with a gradient of Hex/EtOAc(25:1-15:1) to afford 1.01 g (71%) of the titled compound, Rf=0.49 (3:1Hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) δ0.98 (s, 9H), 2.40 (s, 3H), 4.01 (s, 1H), 7.24(d, 1H), 7.26 (d, 1H), 7.48 (d, 2H), 7.54 (d, 2H); FAB mass spectrum,m/e 310 (M+1, calcd for C₁₅ H₁₉ S₂ O₂ N, 310)

Step E: Preparation of2-(4-bromomethylphenyl)-3-t-butylsulfonamidothiophene (scheme II-7,compound 7f, Y=S)

To a solution of the product of Step D (201 mg, 0.651 mmol) under N₂ indry CCl₄ (2.5 mL) was added NBS (130 mg, 0.730 mmol) and a catalyticamount of AIBN. The reaction mixture was brought to reflux (110° C.).After 5 h the reaction was cooled to rt and the insoluable succinimidewas removed by filtration. The solvent was replaced with Et₂ O/EtOAc andwashed with water (2×) and brine, dried over MgSO₄ and filtered. Thesolvent was removed and the crude reaction product dried thoroughlyunder vacuum.

Step F: Preparation of2-Butyl-6-methyl-3-[[4-[3-(N-t-butylsulfonamido)-2-thienyl]phenyl]methyl]quinazolin-4(3H)-one[compound 9b, scheme II-9, where X¹ --X² --X³ X⁴ =--S--CH--CH--CZ--Z=SO₂ NHtBu]

To a solution of 2-butyl-6-methylquinazolin-4(1H)-one, the product ofExample 1, in dry DMF under N₂ is added NaH. The reaction is allowed tostir for 30 min. To this is added a solution of the product of Step E(crude) in dry DMF. After about 5 h the reaction is quenched with sat'dNH₄ Cl solution. The DMF is replaced with Et₂ O/EtOAc, dried over MgSO₄and the insoluable salts removed by filtration. The product was purifiedby flash chromatography on a silica column.

Step G: Preparation of2-Butyl-6-methyl-3-[[4-[3-(N-t-benzoylsulfonamido)-2-thienyl]phenyl]methyl]quinazolin-4(3H)-one[compound 9b, scheme II-9, where X¹ --X² --X³ X⁴ =--S--CH--CH--CZ--Z=SO₂ NHCOPh

Part 1: To dry product of Step F is added anisole (2 drops) and TFA andthe reaction is allowed to stir overnight. The next day the TFA isremoved and the reaction became a deep red color. The product can bepurified by flash chromatography on a silica column. Removal of thesolvent affords the primary sulfonamide.

Part 2: Acylation with benzoylchloride was carried out following theprocedure used in part 2, Step E of Example 25.

EXAMPLE 275-Butyl-2-(2-chlorophenyl)-4-[[4-[3-(N-benzoylsulfonamido)-2-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Compound 20 of Table V) Step A: A preparation of5-butyl-2-(2-chlorophenyl)-4-[[4-[3-(N-t-butylsulfonamido)-2-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of5-butyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one theproduct of Example 17, (101 mg, 0.400 mmol) in dry DMF (1 mL) under N₂was added NaH (16.0 mg, 0.400 mmol). The reaction was allowed to stirfor 30 min. The reaction turned pink in color. To this was added asolution of the product of Example 26, Step E (0.415 mmol, crude) in dryDMF (1.5 mL). After 5 h the reaction was quenched with sat'd NH₄ Clsolution. The DMF was replaced with EtOAc, dried over MgSO₄ and theinsoluable salts removed by filtration. The product was purified byflash chromatography on a silica column using Hex/EtOAc (2:1) to afford120 mg (52% 2 steps) of the desired product, Rf=0.29 (2:1EtOAc/Hex). FABmass spectrum, m/e 559.3 (M+1, calcd for C₂₇ H₃₁ S₂ O₃ N₄ Cl 559.5).

¹ H NMR (400 MHz, CD₃ OD) δ0.89 (t, 3H), 1.00 (s, 9H), 1.35-1.41(sextet, 2H), 1.58-1.62 (quintet, 2H), 2.58 (t, 2H), 5.05 (s, 2H),7.39-7.66 (m, 10 H).

Step B: Preparation of5-butyl-2-(2-chlorophenyl)-4-[[4-[3-sulfonamido-2-thienyl]phenyl]methyl]-2,4-dihydro-1,2,4-triazol-3-one

To the dry product of Step A (60 mg, 0.11 mmol) was added anisole (2drops) and TFA (2 mL) and the reaction was allowed to stir over twodays. The reaction became a deep red color. The TFA was removed and theproduct was free based by eluting through a silica column using CHCl₃/MeOH/NH₄ OH (80:10:1) to afford 48.2 mg (87%) of the desired product asa white solid, Rf=0.70 (40:10:1 CHCl₃ /MeOH/NH₄ OH).

Step C: Preparation of5-butyl-2-(2-chlorophenyl)-4-[[4-[3-(N-benzoylsulfonamido-2-thienyl]phenyl]methyl]-2,4-dihydro-1,2,4-triazol-3-one

To the product of Step B (21.0 mg, 0.042 mmol) in dry pyridine (0.5 mL)was added benzoylchloride (50 μL, 0.43 mmol) and a catalytic amount ofDMAP. After 1.5 h the sides of the flask were rinsed with additionalpyridine (1 mL) and the reaction allowed to stir another 30 min. Thereaction was concentrated then diluted with CH₂ Cl₂ and washed with 10%citric acid (2×) and water, dried over MgSO₄, filtered and the solventremoved. The product was purified by flash chromatography on a silicacolumn using CHCl₃ /MeOH/NH₄ OH (80:10:1). Purification yielded 21.2 mg(83%) of the titled compound, Rf=0.39 (40:10:1 CHCl₃ /MeOH/NH₄ OH). FABmass spectrum, m/e 629.6 (M+Na, calcd for C₃₀ H₂₇ S₂ O₄ OH). FAB massspectrum, m/e 629.6 (M+Na, calcd for C₃₀ H₂₇ S₂ O₄ N₄ Cl 629.5).

¹ H NMR (400 MHz, CDCl₃) δ0.88 (t, 3H), 1.35-1.40 (sextet, 2H),1.59-1.64 (quintet, 2H), 2.56 (t, 2H), 5.02 (s, 2H), 7.33-7.63 (m, 15H).

EXAMPLE 28 2-(2-chlorophenyl)-5-butyl-4-[[4-[3-N-cyclopropanecarbonylsulfonamido-2-thienyl]phenyl]methyl]-2,4-dihydro-1,2,4-triazol-3-one

To the product of Example 27, Step B (20.8 mg, 0.041 mmol) in drypyridine (0.5 mL) was added cyclopropane carbonyl chloride (38 μL, 0.41mmol) and a catalytic amount of DMAP. After 3 h in the sides of theflask were rinsed with additional pyridine (1 mL) and the reactionallowed to stir another 2 h. The reaction was diluted with CH₂ Cl₂ andwashed with 10% citric acid (2×) and water, dried over MgSO₄, filteredand the solvent removed. The product was purified by flashchromatography on a silica column using CHCl₃ /MeOH/NH₄ OH (80:10:1).Purification yielded 16.5 mg (71%) of the titled compound, Rf=0.52(40:10:1 (CHCl₃ /MeOH/NH₄ OH). FAB mass spectrum, m/e 571.3 (M+1, clacdfor C₂₇ H₂₇ S₂ O₄ N₄ Cl 571.5).

¹ H NMR (400 MHz, CD₃ OD) δ0.68-0.75 (m, 4H), 0.89 (t, 3H), 1.34-1.41(m, 3H), 1.58-1.63 (m, 2H), 2.60 (quintet, 2H), 5.05 (s, 2H), 7.39 (d,2H), 7.46-7.63 (m, 8H).

EXAMPLE 29 A representative procedure for the preparation of compoundsof Structure 11-d, Scheme II-11 Step 1: Preparation of2-pentyl-5-(t-butylsulfonamido)thiophene (scheme II-11, compound 11a,R¹² =(CH₂)₄ CH₃)

To a solution of 2-(t-butylsulfonamido)thiophene (3.42 g, 15.6 mmol) inanhydrous THF cooled to -78° C. under N₂ was added 2.5M n-BuLi (15.6 mL,2.5 equiv). The reaction was warmed to -20° C. over 3.5 h. Afterstirring at -20° C. for an addional h, iodopentane (2.4 mL, 1.2 equiv)was added. The ice bath was removed and the reaction was stirred at rtovernight. The next day the reaction was quenched with sat'd NH₄ Clsolution and the THF was removed in vacuo. The residue was extractedwith Et₂ O/EtOAc and washed with water and brine. The organic was driedover anhydrous MgSO₄ and concentrated in vacuo. The product was purifiedby flash chromatography on a silica column eluting with Hex/EtOAc(15:1). Removal of the solvent afforded 2.72 g (60%) of the titledcompound as a yellow oil. Rf=0.4 (6:1 Hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) δ0.91 (t, 3H), 1.28 (s, 9H), 1.33 (m, 4H), 1.68(bt, 2H), 2.81 (t, 2H), 4.63 (s, 1H), 6.69 (d, 1H), 7.41 (d, 1H).

The following table lists additional compounds (11a, scheme II-11)prepared using the procedure described above. Any variation from theabove procedure is noted in the comment column.

    __________________________________________________________________________    Compounds 11a, Scheme II-11                                                   R.sup.12                                                                              R.sup.12 X                                                                            % Yield                                                                            Rf (solvent)                                                                             Comments                                      __________________________________________________________________________    CH.sub.3                                                                              ICH.sub.3                                                                             49   0.44 (3:1 Hex/EtOAc)                                                                     *, white solid, ↑                       CH.sub.2 CH.sub.3                                                                     ICH.sub.2 CH.sub.3                                                                    84   0.47 (3:1 Hex/EtOAc)                                                                     *, oil                                        (CH.sub.2).sub.2 CH.sub.3                                                             I(CH.sub.2).sub.2 CH.sub.3                                                            65   0.52 (2:1 Hex/EtOAc)                                                                     *, oil                                        (CH.sub.2).sub.3 CH.sub.3                                                             I(CH.sub.2).sub.3 CH.sub.3                                                            62   0.32 (6:1 Hex/EtOAc)                                                                     *, yellow oil, @                              CH.sub.2 CH(CH.sub.3).sub.2                                                           ICH.sub.2 CH(CH.sub.3).sub.2                                                          44   0.37 (6:1 Hex/EtOAc)                                                                     *, yellow oil, #                              (CH.sub.2).sub.4 CH.sub.3                                                             I(CH.sub.2).sub.4 CH.sub.3                                                            60   0.40 (6:1 Hex/EtOAc)                                                                     *, yellow oil                                 CH.sub.2 Ph                                                                           BrCH.sub.2 Ph                                                                         ˜70                                                                          0.49 (3:1 Hex/EtOAc)                                                                     taken on crude                                Si(CH.sub.3).sub.3                                                                    ClSi(CH.sub.3).sub.3                                                                  60   0.36 (6:1 Hex/EtOAc)                                                                     *, solid, @                                   __________________________________________________________________________     * The high field NMR spectrum and FAB mass spectrum are consistant with       the structure assigned.                                                       # Yield is based on recovered starting material.                              @ A 1.5 M LDA solution was substituted for NBuLi.                             ↑ MPLC purification was necessary.                                 

Step 2: Preparation of boronic acid derivative 11b (scheme II-11,compound 11b, R¹² =(CH₂)₄ CH₃)

To a solution of 2-pentyl-5-(t-butylsulfonamido)thiophene (2.50 g, 8.65mmol) in anhydrous THF (15 mL) cooled to -78° C. was added 2.5M n-BuLi(8.7 mL, 2.5 equiv). The mixture was allowed to warm to rt over 4 h andstirred for an additional 30 min. The mixture was cooled back to -60° C.and triisopropyl borate (3.0 mL, 1.5 equiv) was added. The ice bath wasremoved and the mixture was stirred overnight at rt. The next day thereaction was quenched with 2N HCL (3 mL) and the resulting mixture wasstirred for 30 min. The THF was removed under reduced pressure and theresidue was taken up into EtOAc. The organic was washed with H₂ O andbrine and dried over MgSO₄. Removal of the solvent afforded 3.2 g(crude) of the titled compound as a thick yellow oil.

Step 3: Preparation of 4-[(4-hydroxymethyl)phenyl]-2-pentyl-5-(t-butylsulfonamido)thiophene (scheme II-11, compound 11c, R¹² =(CH₂)₄CH₃)

To a solution of the product from step A (3.2 g, crude) in toluene (60mL) and 1N NaOH (17 ml) was added 4-bromobenzyl alcohol (4.85 g, 3equiv) in EtOH (15 mL). To this mixture was added Pd(PPh₃)₄ (300 mg, 3mol %). The reaction was stirred at reflux under N₂ for 4 h. The mixturewas cooled to rt and extracted with Et₂ O/EtOAc. The organic was washedwith H₂ O and brine, dried over anhydrous MgSO₄ and concentrated invacuo. The product was purified by flash chromatography on a silicacolumn eluting with Hex/EtOAc (2:1). Removal of the solvent afforded1.97 g (58%) of the titled compound as a slightly yellow solid. Rf=0.24(2:1 Hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) δ0.91 (t, 3H), 1.01 (s, 9H), 1.35 (m, 4H), 1.67(bm, 3H), 2.82 (t, 2H), 4.13 (s, 1H), 4.75 (s, 2H), 6.77 (s, 1H), 7.44(d, 2H), 7.60 (d, 2H).

Step 4: Preparation of4-[4-bromomethyl)phenyl]-2-pentyl-5-(t-butylsulfonamido)thiophene(scheme II-11, compound 11d, R¹² =(CH₂)₄ CH₃)

To a solution of the product of step B (493 mg, 1.25 mmol) in anhydrousCCl₄ (4 mL) and CH₂ Cl₂ (4 mL) was added PBr₃ (0.078 mL, 0.66 equiv).After stirring at rt for 1 h the solvent was removed under reducedpressure and the residue was stripped down fom CCl₄ several times toremove any residual HBr. The product was purified by flashchromatography on a silica column eluting with Hex/EtOAc (2:1). Removalof the solvent afforded 473 mg (83%) of the titled compound as aslightly yellow solid. Rf=0.72 (2:1 Hex/EtOAc).

¹ H NMR (200 MHz, CDCl₃) δ0.90 (t, 3H), 0.99 (s, 9H), 1.35 (m, 4H), 1.71(m, 2H), 2.81 (t, 2H), 4.05 (s, 1H), 4.52 (s, 2H), 6.77 (s, 1H), 7.45(d, 2H), 7.59 (d, 2H).

The following table lists additional compounds (11d, scheme II-11)prepared using the procedure described above. Any variation from theabove procedure is noted in the comment column.

    __________________________________________________________________________    Compounds 11d, Scheme II-11                                                           Pd Coupling                                                           R.sup.12                                                                              Yield   Rf (solvent) Comments                                         __________________________________________________________________________    CH.sub.3                                                                              27      0.67 (2:1 Hex/EtOAc)                                                                       *, #, white solid                                CH.sub.2 CH.sub.3                                                                     23      0.70 (2:1 Hex/EtOAc)                                                                       taken on crude                                   (CH.sub.2).sub.2 CH.sub.3                                                             52      0.44 (1:1 Hex/EtOAc)                                                                       *, yellowish solid                               (CH.sub.2).sub.3 CH.sub.3                                                             30      0.73 (2:1 Hex/EtOAc)                                                                       *, #, yellowish solid                            CH.sub.2 CH(CH.sub.3).sub.2                                                           28      0.25 (2:1 Hex/EtOAc 2×'s                                                             *, #, yellowish solid                            (CH.sub.2).sub.4 CH.sub.3                                                             58      0.40 (6:1 Hex/EtOAc)                                                                       *, yellowish solid                               CH.sub.2 Ph                                                                           25      0.54 (3:1 Hex/EtOAc)                                                                       *, #, white solid                                Si(CH.sub.3).sub.3                                                                    36      0.45 (6:1 Hex/EtOAc)                                                                       *, @, white solid                                __________________________________________________________________________     * The high field NMR spectrum and FAB mass spectrum are consistant with       the structure assigned.                                                       # The palladium catalyzed coupling was done using anhydrous DMF as solven     with NEt.sub.3 as base.                                                       @ 4bromotoluene was substituted for 4bromobenzyl alcohol in the palladium     coupling (step B) and NBS bromination was used to prepare the                 corresponding bromide.                                                   

EXAMPLE 305-butyl-2-(2-trifluoromethylphenyl)-3-[[4-[2-(N-benzoylsulfonamido)-5-methyl-3-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Compound 28 of Table V)

The titled compound was prepared from compound 11d (R¹² =CH₃)substituting5-butyl-2-(2-trifluoromethylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-onefor 5-butyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one andusing the procedure described in Steps A through C of Example 27.

¹ H NMR (400 MHz, CD₃ OD) δ0.87 (t, 3H), 1.32 (q, 2H), 1.59 (m, 2H),2.51 (s, 3H), 2.52 (t, 2H), 4.61 (s, 1H), 4.94 (s, 2H), 6.82 (s, 1H),7.23 (d, 2H), 7.29 (d, 2H), 7.41 (m, 1H), 7.56-7.67 (comp m, 5H), 7.70(t, 1H), 7.81 (t, 1H), 7.89 (d, 1H).

EXAMPLE 315-butyl-2-(2-trifluoromethylphenyl)-3-[[4-[2-(N-benzoylsulfonamido)-5-ethyl-3-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Compound 29 of Table V)

The titled compound was prepared from compound 11d (R¹² =CH₂ CH₃) usingthe procedure described in Example 30.

¹ H NMR (400 MHz, CDCl₃) δ0.80 (t, 3H), 1.22 (q, 2H), 1.24 (t, 3H), 1.51(t, 2H), 2.31 (t, 2H), 2.65 (q, 2H), 4.68 (s, 2H), 6.63 (s, 1H), 7.03(bd, 2H), 7.16 (bd, 2H), 7.32 (m, 2H), 7.38-7.51 (comp m, 4H), 7.61 (d,1H), 7.71 (bs, 1H).

EXAMPLE 325-butyl-2-(2-trifluoromethylphenyl)-3-[[4-[2-(N-benzoylsulfonamido)-5-propyl-3-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Compound 30 of Table V)

The titled compound was prepared from compound 11d (R¹² =(CH₂)₂ CH₃)using the procedure described in Example 30.

¹ H NMR (400 MHz, CD₃ OD) δ0.86 (t, 3H), 0.98 (q, 3H), 1.33 (m, 2H),1.61 (m, 2H), 1.68 (m, 2H), 2.52 (t, 2H), 2.78 (t, 2H), 4.95 (s, 2H),6.82 (s, 1H), 7.22 (d, 4H), 7.38-7.61 (comp m, 5H), 7.72 (dd, 4H).

EXAMPLE 335-butyl-2-(2-trifluoromethylphenyl)-3-[[4-[2-(N-benzoylsulfonamido)-5-n-butyl-3-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Compound 31 of Table V)

The titled compound was prepared from compound 11d (R¹² =(CH₂)₃ CH₃)using the procedure described in Example 30.

¹ H NMR (400 MHz, CD₃ OD) δ0.87 (t, 3H), 0.96 (t, 3H), 1.32-1.81 (compm, 8H), 2.51 (t, 2H), 2.88 (t, 2H), 5.01 (s, 2H), 6.87 (s, 1H), 7.23 (d,2H), 7.31 (d, 2H), 7.48 (d, 2H), 7.58 (bd, 4H), 7.70-7.82 (comp m, 2H),7.88 (d, 1H).

EXAMPLE 345-butyl-2-(2-trifluoromethylphenyl)-3-[[4-[2-(N-benzoylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Compound 33 of Table V)

The titled compound was prepared from compound 11d (R¹² =CH₂ CH(CH₃)₂)using the procedure described in Example 30.

¹ H NMR (400 MHz, CD₃ OD) δ0.87 (t, 3H), 1.00 (d, 6H), 1.30 (m, 2H),1.59 (m, 2H), 1.96 (m, 2H), 2.52 (t, 2H), 2.73 (d, 2H), 5.00 (s, 2H),6.86 (s, 1H), 7.27 (d, 2H), 7.33 (d, 2H), 7.47 (d, 3H), 7.58 (bd, 3H),7.70-7.82 (comp m, 2H), 7.91 (d, 1H).

EXAMPLE 355-butyl-2-(2-trifluoromethylphenyl)-3-[[4-[2-(N-benzoylsulfonamido)-5-pentyl-3-thienyl]phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Compound 32 of Table V)

The titled compound was prepared from compound 11d (R¹² =(CH₂)₄ CH₃)using the procedure described in Example 30.

¹ H NMR (200 MHz, CD₃ OD) δ0.82-0.95 (comp m, 6H), 1.21-1.51 (comp m,4H), 1.61 (m, 2H), 1.71 (m, 2H), 2.52 (t, 2H), 2.87 (t, 2H), 4.99 (s,2H), 6.87 (s, 1H), 7.27 (d, 2H), 7.38 (d, 2H), 7.47 (d, 2H), 7.57 (bd,4H), 7.70-7.82 (comp m, 2H), 7.89 (d, 1H).

EXAMPLE 362-propyl-6-(3-N-ethylurea)-3-[[4-[2-(N-butyloxycarbonylsulfonamido)-5-propyl-3-thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 46 of Table VII)

The titled compound was prepared from compound 18c of scheme II-18 where--X¹ --X² --X³ --X⁴ -- is --CH═CR¹² --S--CZ═, Z=SO₂ NH₂, R¹² =propyl andR²¹ is Et. To a solution of 18c (32 mg, 0.056 mmol) in dry pyridine (1.0mL) was added n-butyl chloroformate (0.1 mL, 0.78 mmol) at rt. Afterstirring at rt overnight, the mixture was diluted with 1N HCl andextracted with ethyl acetate. The organic extract was dried overanhydrous Na₂ SO₄, evaporated in vacuo and the residue was purified bysilica gel chromatotron plate (CH₂ Cl₂ /MeOH 40:1) to afford 38 mg(100%) of the titled compound as a colorless glass.

¹ H NMR (200 MHz, CD₃ OD) δ0.62 (t, 3H), 0.72-0.93 (comp m, 6H), 0.95(t, 3H), 1.03 (m, 2H), 1.22 (m, 2H), 1.45-1.68 (comp m, 4H), 2.57 (q,4H), 3.03 (q, 2H), 3.73 (t, 2H), 5.21 (s, 2H), 6.55 (s, 1H), 6.96 (d,2H), 7.22 (d, 2H), 7.39 (l, 1H), 7.81 (s, 2H).

EXAMPLE 372-propyl-6-(N-benzamido)-3-[[4-[2-N-cyclopropylcarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 42 of Table VII)

The titled compound was prepared using the methodology described inscheme II-17 from compound 17e where --X¹ --X² --X³ --X⁴ -- is --CH═CR¹²--S--CZ═, Z=SO₂ NH₂, R¹² =isobutyl and R²¹ is Ph.

¹ H NMR (200 MHz, CDCl₃) δ0.62-0.72 (m, 2H), 0.85-1.08 (comp m, 11H),1.55-1.98 (m, 4H), 2.56 (t, 2H), 2.67 (d, 2H), 4.97 (s, 2H), 6.68 (s,1H), 6.87 (d, 2H), 7.56-7.71 (comp m, 5H), 7.69 (d, 1H), 7.85 (d, 2H),8.40 (d, 1H), 8.71 (dd, 1H), 9.61 (bs, 1H).

EXAMPLE 382-propyl-6-(N-benzamido)-3-[[4-[2-N-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 43 of Table VII)

The titled compound was prepared using the methodology described inscheme II-17 from compound 17e where --X¹ --X² --X³ --X⁴ -- is --CH═CR¹²--S--CZ═, Z=SO₂ NH₂, R¹² =isobutyl and R²¹ is Ph.

¹ H NMR (200 MHz, CDCl₃) δ0.78-0.88 (comp m, 6H), 0.93 (d, 6H), 1.23 (m,2H), 1.51 (m, 2H), 1.68 (m, 2H), 1.91 (m, 1H), 2.50 (t, 2H), 2.67 (d,2H), 4.11 (t, 2H), 4.96 (s, 2H), 6.69 (s, 1 H), 6.74 (d, 2H), 7.32 (d,2H), 7.41-7.59 (comp m, 3H), 7.68 (d, 1H), 8.42 (d, 1H), 8.89 (dd, 1H),9.61 (bs, 1H).

EXAMPLE 392-propyl-6-(3-N-ethylurea)-3-[[4-[2-(N-methoxyethoxycarbonylsulfonamido)-5-propyl-3-thienyl]phenyl]methyl]quinazolin-4-(3H)-one(Compound 48 of Table VII)

The titled compound was prepared from compound 18c of scheme II-18 where--X¹ --X² --X³ --X⁴ -- is --CH═CR¹² --S--CZ═, Z=SO₂ NH₂, R¹² =propyl andR²¹ is ethyl.

¹ H NMR (200 MHz, CD₃ OD) δ0.72-0.86 (comp m, 6H), 0.92 (t, 3H), 1.52(m, 4H), 3.01 (q, 2H), 3.04 (s, 3H), 3.23 (t, 2H), 3.91 (t, 2H), 5.21(s, 2H), 6.52 (s, 1H), 6.96 (d, 2H), 7.21 (d, 2H), 7.39 (l, 1H), 7.79(s, 2H).

DEPROTECTION OF THE TRITYL GROUP ON THE TETRAZOLE RING

To a solution of of the trityl protected product in MeOH is added acatalytic amount of 2N HCl. After about an hour the solvent is removedand the product triturated with Et₂ O to will afford the free tetrazole.

                                      TABLE V                                     __________________________________________________________________________     ##STR74##                                                                    # R.sup.1                                                                            R.sup.16                                                                            X.sup.1X.sup.2X.sup.3X.sup.4                                                                  R.sup.12                                                                           Z                                           __________________________________________________________________________     1                                                                              n-propyl                                                                           CH.sub.2 Ph                                                                         CHSCHCZ              1H-tetrazol-5-yl                             2                                                                              n-butyl                                                                            CH.sub.2 Ph                                                                         CHSCHCZ              1H-tetrazol-5-yl                             3                                                                              n-propyl                                                                           cyclopentyl                                                                         CHSC(Br)CZ           1H-tetrazol-5-yl                             4                                                                              n-butyl                                                                            n-butyl                                                                             CHSC(Br)CZ           1H-tetrazol-5-yl                             5                                                                              n-butyl                                                                            CO.sub.2 CH.sub.3                                                                   CHCHOCZ              1H-tetrazol-5-yl                             6                                                                              n-butyl                                                                            CH.sub.2 OH                                                                         CHCHOCZ              1H-tetrazol-5-yl                             7                                                                              n-butyl                                                                            2-CO.sub.2 H-Ph                                                                      CHSCHCZ             SO.sub.2 NHCOPh                              8                                                                              n-butyl                                                                            2-Cl-Ph                                                                             CHSCHCZ              CO.sub.2 H                                   9                                                                              n-propyl                                                                           CO.sub.2 CH.sub.3                                                                   CHSCHCZ              1H-tetrazol-5-yl                            10                                                                              n-propyl                                                                           CH.sub.2 Ph                                                                         CHSCHCZ              SO.sub.2 NHCOPh                             11                                                                              n-propyl                                                                           CH.sub.2 Ph                                                                         CHCHSCZ              1H-tetrazol-5-yl                            12                                                                              n-butyl                                                                            CH.sub.2 Ph                                                                         CHCHSCZ              1H-tetrazol-5-yl                            13                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHSCHCZ              SO.sub.2 NHCOPh                             14                                                                              n-butyl                                                                            2-CH.sub.3 -Ph                                                                      CHSCHCZ              SO.sub.2 NHCOPh                             15                                                                              n-propyl                                                                           2-Cl-Ph                                                                             CHSCHCZ              SO.sub.2 NHCOPh                             16                                                                              n-propyl                                                                           CH.sub.2 Ph                                                                         CHCHSCZ              SO.sub.2 NHCOPh                             17                                                                              n-butyl                                                                            CH.sub.2 Ph                                                                         CHCHSCZ              SO.sub.2 NHCOPh                             18                                                                              n-propyl                                                                           2-Cl-Ph                                                                             CHSCHCZ              SO.sub.2 NHCOPh                             19                                                                              n-propyl                                                                           2-Cl-Ph                                                                             SCHCHCZ              SO.sub.2 NHCOPh                             20                                                                              n-butyl                                                                            2-Cl-Ph                                                                             SCHCHCZ              SO.sub.2 NHCOPh                             21                                                                              n-butyl                                                                            CH.sub.2 OH                                                                         CHSC(SO.sub. 2 NHCOPh)CZ                                                                           SO.sub.2 NHCOPh                             22                                                                              n-butyl                                                                            CH.sub.2 CH.sub.3                                                                   CHSCHCZ              1H-tetrazol-5-yl                            23                                                                              n-butyl                                                                            CH.sub.2 Ph                                                                          ##STR75##           1H-tetrazol-5-yl                            24                                                                              n-butyl                                                                            2-Cl-Ph                                                                              ##STR76##           SO.sub.2 NHCOPh                             25                                                                              n-propyl                                                                           2-CF.sub.3 -Ph                                                                       ##STR77##           SO.sub.2 NHCOPh                             26                                                                              n-butyl                                                                            2,6-diCl-Ph                                                                          ##STR78##           SO.sub.2 NHCOPh                             27                                                                              n-butyl                                                                            2-Cl-Ph                                                                             SCHCHCZ                                                                                             ##STR79##                                  28                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  methyl                                                                             SO.sub.2 NHCOPh                             29                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  ethyl                                                                              SO.sub.2 NHCOPh                             30                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  n-propyl                                                                           SO.sub.2 NHCOPh                             31                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  n-butyl                                                                            SO.sub.2 NHCOPh                             32                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  n-pentyl                                                                           SO.sub.2 NHCOPh                             33                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  isobutyl                                                                           SO.sub.2 NHCOPh                             34                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  methyl                                                                             SO.sub.2 NHCOCH(Ph).sub.2                   35                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  ethyl                                                                              SO.sub.2 NHCOCH(Ph).sub.2                   36                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  n-propyl                                                                           SO.sub.2 NHCOCH.sub.2 OMe                   37                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  isobutyl                                                                           SO.sub.2 NHCO(3-Me-2-furyl)                 38                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  n-pentyl                                                                           SO.sub.2 NHCO(3-Me-2-furyl)                 39                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  n-propyl                                                                           SO.sub.2 NHCOtBu                            40                                                                              n-butyl                                                                            2-CF.sub.3 -Ph                                                                      CHCR.sup.12SCZ  isobutyl                                                                           SO.sub.2 NHCOtBu                            __________________________________________________________________________

                                      TABLE VI                                    __________________________________________________________________________     ##STR80##                                                                    # R.sup.1                                                                            R.sup.17                                                                           R.sup.18                                                                           X.sup.1X.sup.2X.sup.3X.sup.4                                                                    R.sup.12                                                                           Z                                     __________________________________________________________________________     1                                                                              n-butyl                                                                            CH.sub.3                                                                           H    CHSCHCZ                1H-tetrazol-5-yl                       2                                                                              n-butyl                                                                            CH.sub.3                                                                           H    CHSCHCZ                SO.sub.2 NHCOPh                        3                                                                              n-propyl                                                                           2-Cl-Ph                                                                            H    CHSCHCZ                SO.sub.2 NHCOPh                        4                                                                              n-butyl                                                                            CH.sub.3                                                                           CH.sub.3                                                                           CHSCHCZ                SO.sub.2 NHCOPh                        5                                                                              n-propyl                                                                           2-CH.sub.3 -Ph                                                                     CH.sub.3                                                                           CHSCHCZ                1H-tetrazol-5-yl                       6                                                                              n-propyl                                                                           2-CF.sub.3 -Ph                                                                     CH.sub. 3                                                                          CHSCHCZ                1H-tetrazol-5-yl                       7                                                                              n-butyl                                                                            2-CH.sub.3 -Ph                                                                     CH.sub.3                                                                           CHC(Si(CH.sub.3).sub.3)SCZ                                                                           SO.sub.2 NHCOPh                        8                                                                              n-propyl                                                                           CH.sub.3                                                                           CH.sub.3                                                                            ##STR81##             SO.sub.2 NHCOPh                        9                                                                              n-butyl                                                                            2-Cl-Ph                                                                                  ##STR82##             SO.sub.2 NHCOPh                       10                                                                              n-propyl                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CHCHSCZ                SO.sub.2 NHCOPh                       11                                                                              n-propyl                                                                           CH.sub.3                                                                           CO.sub.2 H                                                                         CHCHSCZ                SO.sub.2 NHCOPh                       12                                                                              n-butyl                                                                            CH.sub.3                                                                           CH.sub.3                                                                           SCHCHCZ                1H-tetrazol-5-yl                      13                                                                              n-butyl                                                                            CH.sub.3                                                                           CO.sub.2 H                                                                         SCHCHCZ                1H-tetrazol-5-yl                      14                                                                              n-butyl                                                                            2-Cl-Ph                                                                            CH.sub.3                                                                           SCHCHCZ                SO.sub.2 NHCOPh                       15                                                                              n-propyl                                                                           2-CH.sub.3 -Ph                                                                     CH.sub.3                                                                           SCHCHCZ                SO.sub.2 NHCOPh                       16                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CH.sub.3 -Ph                                                                     CHSC(SO.sub.2 NHCOPh)-CZ                                                                             H                                     17                                                                              n-propyl                                                                           CH.sub.3                                                                           Cl   CHSCHCZ                1H-tetrazol-5-yl                      18                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CH.sub.3 -Ph                                                                     CHSCHCZ                1H-tetrazol-5-yl                      19                                                                              n-propyl                                                                           CH.sub.3                                                                           2-Cl-Ph                                                                            CHSC(Br)CZ             1H-tetrazol-5-yl                      20                                                                              n-propyl                                                                           CH.sub.3                                                                           CH.sub.2 -Ph                                                                       CHSC(Br)CZ             1H-tetrazol-5-yl                      21                                                                              n-propyl                                                                           CH.sub.3                                                                           2-Cl-Ph                                                                            CHCHSCZ                1H-tetrazol-5-yl                      22                                                                              n-propyl                                                                           CH.sub.3                                                                           CH.sub.2 -Ph                                                                       CHCHSCZ                1H-tetrazol-5-yl                      23                                                                              n-butyl                                                                            CH.sub.3                                                                           2-Cl-Ph                                                                            CHCHOCZ                1H-tetrazol-5-yl                      24                                                                              n-butyl                                                                            CH.sub.3                                                                           CH.sub.2 -Ph                                                                       CHCHOCZ                1H-tetrazol-5-yl                      25                                                                              n-propyl                                                                           CH.sub.3                                                                           2-Cl-Ph                                                                             ##STR83##             SO.sub.2 NHCOPh                       26                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                      ##STR84##             SO.sub.2 NHCOPh                       27                                                                              n-butyl                                                                            CH.sub.3                                                                           CH.sub.2 -Ph                                                                       CHCHSCZ                SO.sub.2 NHCOPh                       28                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CH.sub.3 -Ph                                                                     CHCHSCZ                SO.sub.2 NHCOPh                       29                                                                              n-butyl                                                                            CH.sub.3                                                                           2-Cl-Ph                                                                            SCHCHCZ                SO.sub.2 NHCOPh                       30                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     SCHCHCZ                SO.sub.2 NHCOPh                       31                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    n-propyl                                                                           SO.sub.2 NHCOPh                       32                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    n-propyl                                                                           SO.sub.2 NHCO.sub.2 Bu                33                                                                              n-butyl                                                                            2-CH.sub.3 -Ph                                                                     2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    n-propyl                                                                           SO.sub.2 NHCO.sub.2 Bu                34                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    isobutyl                                                                           SO.sub.2 NHCO.sub.2 Bu                35                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    isobutyl                                                                           SO.sub.2 NHCOPh                       36                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    isobutyl                                                                           SO.sub.2 NHCOn-pentyl                 37                                                                              butyl                                                                              CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    ethyl                                                                              SO.sub.2 NHCO.sub.2 Bu                38                                                                              n-butyl                                                                            CH.sub.3                                                                           2-CF.sub.3 -Ph                                                                     CHCR.sup.12SCZ    propyl                                                                             SO.sub.2 NHCONHBu                     __________________________________________________________________________

                                      TABLE VII                                   __________________________________________________________________________     ##STR85##                                                                    # R.sup.1                                                                            R.sup.8a   X.sup.1X.sup.2X.sup.3X.sup.4                                                                     R.sup.12                                                                            Z                                  __________________________________________________________________________     1                                                                              n-butyl                                                                            H          CHSCHCZ                  1H-tetrazol-5-yl                    2                                                                              n-butyl                                                                            Me         CHSCHCZ                  1H-tetrazol-5-yl                    3                                                                              n-butyl                                                                            N(Me)(CO.sub.2 Me)                                                                       CHSCHCZ                  1H-tetrazol-5-yl                    4                                                                              n-propyl                                                                           Me         CHSCHCZ                  1H-tetrazol-5-yl                    5                                                                              n-propyl                                                                           N(Me)(CO.sub.2 Me)                                                                       CHSCHCZ                  1H-tetrazol-5-yl                    6                                                                              n-butyl                                                                            N(Me)(CO.sub.2 Me)                                                                       CHSCHCZ                  SO.sub.2 NHCOPh                     7                                                                              n-propyl                                                                           H          CHSCHCZ                  1H-tetrazol-5-yl                    8                                                                              n-propyl                                                                           H          CHSCHCZ                  SO.sub.2 NHCOPh                     9                                                                              n-butyl                                                                            N(Me)(CO.sub.2 Me)                                                                       CHSCHCZ                  1H-tetrazol-5-yl                   10                                                                              n-butyl                                                                            N(Me)(CO.sub.2 iBu)                                                                      CHSC(SO.sub.2 NHCOPh)-CZ 1H-tetrazol-5-yl                   11                                                                              n-butyl                                                                            CH.sub.3   SCHCHCZ                  SO.sub.2 NHCOPh                    12                                                                              n-butyl                                                                            CH.sub.3   CHCHSCZ                  SO.sub.2 NHCOPh                    13                                                                              n-propyl                                                                           N(Me)(CO.sub.2 iBu)                                                                      CHCHSCZ                  SO.sub.2 NHCOPh                    14                                                                              n-butyl                                                                            CH.sub.3   CHCHSCZ                  1H-tetrazol-5-yl                   15                                                                              n-propyl                                                                           N(Bz)(CO.sub.2 iBu)                                                                      CHCHSCZ                  1H-tetrazol-5-yl                   16                                                                              n-butyl                                                                            N(Bz)(CO.sub.2 Bu)                                                                       CHSCHCZ                  1H-tetrazol-5-yl                   17                                                                              n-butyl                                                                            CH.sub.3   CHSC(Br)CZ               1H-tetrazol-5-yl                   18                                                                              n-propyl                                                                           CH.sub.3   CHSC(Br)CZ               1H-tetrazol-5-yl                   19                                                                              n-butyl                                                                            N(Boz)(Pn) CHCHSCZ                  1H-tetrazol-5-yl                   20                                                                              n-butyl                                                                            N(Boz)(Bz) CHCHSCZ                  1H-tetrazol-5-yl                   21                                                                              n-butyl                                                                            N(Bz)(CO.sub.2 Pn)                                                                       CHCHSCZ                  1H-tetrazol-5-yl                   22                                                                              n-propyl                                                                           N(Me)(CO.sub.2 iBu)                                                                      CHCHSCZ                  1H-tetrazol-5-yl                   23                                                                              n-butyl                                                                            N(Me)(CO.sub. 2 Me)                                                                      CHCHOCZ                  1H-tetrazol-5-yl                   24                                                                              n-propyl                                                                           N(Bz)(CO.sub.2 iBu)                                                                      CHCHOCZ                  1H-tetrazol-5-yl                   25                                                                              n-butyl                                                                            N(Boz)(Pn) CHCHOCZ                  1H-tetrazol-5-yl                   26                                                                              n-propyl                                                                           N(Bz)(CO.sub.2 Bu)                                                                       CHCHOCZ                  1H-tetrazol-5-yl                   27                                                                              n-butyl                                                                            CH.sub.3   CHCHOCZ                  1H-tetrazol-5-yl                   28                                                                              n-propyl                                                                           CH.sub.3   CHCHOCZ                  1H-tetrazol-5-yl                   29                                                                              n-butyl                                                                            N(Bz)(CO.sub.2 iBu)                                                                      CHSCHCZ                  1H-tetrazol-5-yl                   30                                                                              n-butyl                                                                            N(Me)(CO.sub.2 Me)                                                                       CHSCHCZ                  SO.sub.2 NHCOCF.sub.3              31                                                                              n-butyl                                                                            N(Bz)(CO.sub.2 Me)                                                                       CHSCHCZ                  CO.sub.2 H                         32                                                                              n-butyl                                                                            CH.sub.3   CHSC(SO.sub.2 NHCOCF.sub.3)CZ                                                                          H                                  33                                                                              n-butyl                                                                            CH.sub.3   CHSC(SO.sub.2 NHCOPh)-CZ H                                  34                                                                              n-butyl                                                                            CH.sub.3   CHSC(SO.sub.2 NHCO-4-pyr)-CZ                                                                           H                                  35                                                                              n-propyl                                                                           N(Bz)[CON(Me)(Et)]                                                                       SCHCHCZ                  SO.sub.2 NHCOPh                    36                                                                              n-butyl                                                                            N(Bz)[CON(Me)(Et)]                                                                       SCHCHCZ                  SO.sub.2 NHCOPh                    37                                                                              n-butyl                                                                            N(Me)(CO.sub.2 Me)                                                                       SCHCHCZ                  SO.sub. 2 NHCOPh                   38                                                                              n-butyl                                                                            CH.sub.3                                                                                  ##STR86##               SO.sub.2 NHCOPh                    39                                                                              n-propyl                                                                           N(Me)(CO.sub.2 Me)                                                                        ##STR87##               SO.sub.2 NHCOPh                    40                                                                              n-propyl                                                                           NHCOPh     CHCR.sup.12SCZ     n-propyl                                                                            SO.sub.2 NHCOPh                    41                                                                              n-propyl                                                                           NHCOPh     CHCR.sup.12SCZ     n-propyl                                                                            SO.sub.2 NHCOcyPr                  42                                                                              n-propyl                                                                           NHCOPh     CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCOcyPr                  43                                                                              n-propyl                                                                           NHCOPh     CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCO.sub.2 Bu             44                                                                              n-propyl                                                                           NHCOPh     CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCOn-pentyl              45                                                                              n-propyl                                                                           NHCOPh     CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCOCH.sub.2 OBu          46                                                                              n-propyl                                                                           NHCONHEt   CHCR.sup.12SCZ     n-propyl                                                                            SO.sub.2 NHCO.sub.2 Bu             47                                                                              n-propyl                                                                           NHCONHEt   CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCO.sub.2 Bu             48                                                                              n-propyl                                                                           NHCONHEt   CHCR.sup.12SCZ     n-propyl                                                                            SO.sub.2 NHCO.sub.2 (CH.sub.2).                                               sub. 2 OMe                         49                                                                              n-propyl                                                                           NHCONHEt   CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCO.sub.2 (CH.sub.2).                                               sub.2 OMe                          50                                                                              n-propyl                                                                           NHCONHiPr  CHCR.sup.12SCZ     n-propyl                                                                            SO.sub.2 NHCO.sub.2 Bu             51                                                                              n-propyl                                                                           NHCONHiPr  CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCO.sub.2 Bu             52                                                                              n-propyl                                                                           NHCONHiPr  CHCR.sup.12SCZ     n-propyl                                                                            SO.sub.2 NHCO.sub.2 (CH.sub.2).                                               sub.2 OMe                          53                                                                              n-propyl                                                                           NHCONHiPr  CHCR.sup.12SCZ     isobutyl                                                                            SO.sub.2 NHCOCH.sub.2 OBu          54                                                                              n-propyl                                                                           NHCONHiPr  CHCR.sup.12SCZ     CH.sub.2 OCH.sub.3                                                                  SO.sub.2 NHCO.sub.2 Bu             __________________________________________________________________________     Abbreviations used: Ph = phenyl; Bz = benzyl; iBu = isobutyl; Boz =           benzoyl; Bu = nbutyl Pn = npentyl; Me = methyl; and Et = ethyl.          

FORMULATION EXAMPLES Typical Pharmaceutical Compositions Containing aCompound of the Invention A: Dry Filled Capsules Containing 50 mg ofActive Ingredient Per Capsule

    ______________________________________                                                           Amount per                                                 Ingredient         capsule (mg)                                               ______________________________________                                        2-Butyl-6-methyl-3-[[4-[3-                                                                        50                                                        (1H-tetrazol-5-yl)-4-                                                         thienyl]phenyl]methyl]-                                                       quinazolin-4(3H)-one                                                          Lactose            149                                                        Magnesium stearate  1                                                         Capsule (size No. 1)                                                                             200                                                        ______________________________________                                    

The2-butyl-6-methyl-3-[[4-[3-(1H-tetrazol-5-yl)-thienyl]phenyl]methyl]quinazolin-4(3H)-onecan be reduced to a No. 60 powder and the lactose and magnesium stearatecan then be passed through a No. 60 blotting cloth onto the powder. Thecombined ingredients can then be mixed for about 10 minutes and filledinto a No. 1 dry gelatin capsule.

B: Tablet

A typical table would contain2-butyl-6-methyl-3-[[(4-[3-(1H-tetrazol-5-yl)-4-thienyl]phenyl]methyl]quinazolin-4(3H)-one(25 mg), pregelatinized starch USP (82 mg), microcrystalline cellulose(82 mg) and magnesium stearate (1 mg).

C: Combination Tablet

A typical combination tablet would contain, for example, a diuretic suchas hydrochlorothiazide (25 mg) and2-butyl-6-methyl-3-[[4-[3-(1H-tetrazol-5-yl)-5-thienyl]phenyl]methyl]quinazolin-4(3H)-one(50 mg) pregelatinized starch USP (82 mg), microcrystalline cellulose(82 mg) and magnesium stearate (1 mg).

D: Suppository

Typical suppository formulations for rectal administration can contain2-butyl-6-methyl-3-[[4-[3-(1H-tetrazol-5-yl)-4-thienyl]phenyl]methyl]quinazolin-4(3H)-one(0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethyleneglycol (775-1600 mg). Other suppository formulations can be made bysubstituting, for example, butylated hydroxytoluene (0.04-0.08 mg) forthe disodium calcium edetate and a hydrogenated vegetable oil (675-1400mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like,for the polyethylene glycol. Further, these suppository formulations canalso include another active ingredient such as another antihypertensiveand/or a diuretic and/or an angiotension converting enzyme and/or acalcium channel blocker in pharmaceutically effective amounts asdescribed, for example, in C above.

E: Injection

A typical injectable formulation would contain2-butyl-6-methyl-3-[[4-[3-(1H-tetrazol-5-yl)-4-thienyl]phenyl]methyl]quinazolin-4(3H)-onesodium phosphate dibasic anhydrous (11.4 mg) benzyl alcohol (0.01 ml)and water for injection (1.0 ml). Such as injectable formulation canalso include a pharmaceutically effective amount of another activeingredient such as another antihypertensive and/or a diuretic and/or anangiotension converting enzyme inhibitor and/or a calcium channelblocker.

What is claimed is:
 1. A compound of structural formula I or itspharmaceutically acceptable salt ##STR88## wherein the heterocycle isdefined as: ##STR89## R¹ is: (a) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂-C₆)-alkynyl each of which is unsubstituted or substituted with asubstituent selected from the group consisting of:i) aryl as definedbelow, ii) C₃ -C₇)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH₂, vi)NH(C₁ -C₄)-alkyl, vii) N[(C₁ -C₄)-alkyl]₂, viii) NHSO₂ R², ix) CF₃, x)COOR², or xi) SO₂ NHR^(2a) ; (b) aryl, wherein aryl is defined as phenylor naphthyl, unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of:i) Br, I, Cl, F, ii) (C₁-C₄)-alkyl, iii) (C₁ -C₄)-alkoxy, iv) NO₂ v) CF₃ vi) SO₂ NR^(2a) R^(2a),vii) (C₁ -C₄)-alkylthio, viii) hydroxy, ix) amino, x) (C₃-C₇)-cycloalkyl, or xi) (C₃ -C₁₀)-alkenyl; (c) heteroaryl, whereinheteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, whichcan contain one or two members selected from the group consisting of N,O, S and wherein the heteroaryl is unsubstituted, monosubstituted ordisubstituted with substituents selected from the group consisting of:i)Cl, Br, I, or F, ii) OH, iii) SH, iv) NO₂, v) (C₁ -C₄)-alkyl, vi) (C₂-C₄)-alkenyl, vii) (C₂ -C₄)-alkynyl, viii) (C₁ -C₄)-alkoxy, or xi) CF₃,or (d) (C₁ -C₄)-polyfluoroalkyl; E is:(a) a single bond, (b) --S(O)_(n)(CH₂)_(s) --, or (c) --O--; n is 0 to 2; s is 0 to 5; J¹ is(a)--C(═M)--, (b) J¹ and L are connected together to form a 6-carbonaromatic ring substituted with R^(7a), R^(7b), R^(8a) and R^(8b) or (c)J¹ and L are connected together to form a 6-membered aromatic ringcontaining one nitrogen atom not at J¹, substituted with R^(7a), R^(8a)and R^(8b) ; K¹ is (a)--C(═M)--, (b) K¹ and L are connected together toform a 6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a)and R^(8b), or (c) K¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom, substituted on the carbonatoms with R^(7a), R^(8a) and R^(8b) ; one of a¹ or b¹ is a double bondin structures Ia provided that when J¹ is --C(═M)-- then b¹ is a doublebond and when K¹ is --C(═M)-- then a¹ is a double bond; L is the pointof attachment of the 6-membered fused aromatic ring optionallycontaining one nitrogen atom; M is O, S or NR¹⁵ ; R² is:(a) H, or (b)(C₁ -C₆)-alkyl; R^(2a) is:(a) R², (b) CH₂ -aryl, or (c) aryl; R^(2b)is:(a) R^(2a), or (b) C₃ -C₇ cycloalkyl; R^(2c) is:(a) --SO₂ -(C₁-C₆)-alkyl; (b) --CO-(C₁ -C₆)-alkyl; (c) --SO₂ -(C₃ -C₆)-cycloalkyl, (d)--CO-(C₃ -C₆)-cycloalkyl, (e) --SO₂ -(C₁ -C₄)-polyfluoroalkyl, (f)--CO-aryl, (g) --CO-polyfluoroaryl, (h) --CO-(2- or 3-thienyl), (i)--SO₂ --(2-or 3-thienyl), (j) --CO-(2-, 3- or 4-pyridyl), (k) --CONH-(C₁-C₆)-alkyl, (l) --CON[(C₁ -C₆)alkyl]₂, (m) --CO₂ -(C₁ -C₆)-alkyl, or (n)--CO₂ -(C₃ -C₆)cycloalkyl; R^(7a) and R^(7b) are independently(a) H, (b)(C₁ -C₆)-alkyl, (C₂ -C₆ -alkenyl or (C₂ -C₆)-alkynyl, (c) Cl, Br, I, F,(d) CF₃, or (e) when R^(7a) and R^(7b) are bonded to adjacent carbonatoms, they can be joined to form a phenyl ring; R^(8a) and R^(8b) areindependently(a) H, (b) aryl-(C₁ -C₄)-alkyl, (c) heteroaryl-(C₁-C₄)-alkyl, (d) (C₁ -C₆)-alkyl, which is unsubstituted or substitutedwith a substituent selected from the group consisting of:--CON(R^(2a))₂, --heteroaryl, --S(O)_(n) -R²¹, -tetrazol-5-yl, --CONSHO₂R²¹, --SO₂ NH-heteroaryl, --SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂,--SO₂ NH-CN, --NR^(2a) COOR²¹, --OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy,(C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁ -C₄)-dialkylamino,--COOR^(2a), --CONHR^(2a), --O--COR^(2a), aryl, or ##STR90## (e)--CO-aryl, (f) (C₃ -C₇)-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i)--OR²¹, (j) --SH, (k) --S(O)_(n) -(C₁ -C₄)-alkyl, (l) --COR^(2a), (m)--CO₂ H, (n) --SO₃ H, (o) --NR^(2a) R²¹, (p) --NR^(2a) COR²¹, (q)--NR^(2a) COOR²¹, (r) --SO₂ NHR^(2a), (s) --SO₂ NR² R^(2a), (t) --NO₂,(u) --NHSO₂ CF₃, (v) --CONR^(2a) R²¹, (w) --(C₁ -C₄)-polyfluoroalkyl,(x) --COOR², (y) --SO₃ H, (z) --N(R^(2a))SO₂ R²¹, (aa) --NR^(2a)CONR^(2b) R²¹, (bb) --OC(═O)NR²¹ R^(2a), (cc) --aryl, (dd) --NHSO₂ CF₃,(ee) --SO₂ NH-heteroaryl, (ff) --SO₂ NHCOR²¹, (gg) --CONHSO₂ R²¹, (hh)--PO(OR²)₂, (ii) --tetrazol-5-yl, (jj) --CONH(tetrazol-5-yl), (kk) --SO₂NHCN, or (ll) --heteroaryl; ##STR91## --X¹ --X² --X³ --X⁴ -- is: (a)--Y--CR¹¹ --CR¹² --CZ--, (b) --CR¹¹ --Y--CR¹² --CZ--, (c) --CR¹¹ --CR¹²--Y--CZ--, (d) --Y--CR¹¹ --CZ--CR¹² --, (e) --CR¹¹ --Y--CZ--CR¹² --, or(f) --CR¹¹ --CR¹² --CZ--Y--; Y is: O, S, SO, or SO₂ ; R⁹ and R¹⁰ areeach independently:(a) H, (b) Cl, Br, I, F, (c) NO₂, (d) (C₁ -C₆)-alkyl,(e) (C₁ -C₆)-acyloxy, (f) (C₃ -C₆)-cycloalkyl, (g) (C₁ -C₆)-alkoxy, (h)--NHSO₂ R^(2a), (i) hydroxy-(C₁ -C₄)-alkyl, (j) (C₁ -C₄)-alkyl-aryl, (k)S(O)_(n) -(C₁ -C₄)-alkyl, (n) NR^(2a) R^(2a), (q) CF₃, (r) --SO₂NHR^(2a), (s) furyl, (t) aryl, wherein aryl is phenyl or naphthyl,unsubstituted or substituted with one or two substituents selected fromthe group consisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy,NO₂, CF₃, (C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁-C₄)-alkyl]₂, --CO₂ H, or --CO₂ -(C₁ -C₄)-alkyl, or (u) when R⁹ and R¹⁰are bonded to adjacent carbon atoms, they can be joined to form an arylring; R¹¹ and R¹² are independently:(a) H, (b) Cl, Br, I, F, (c) NO₂,(d) NH₂, (e) NH[(C₁ -C₄)-alkyl], (f) N[(C₁ -C₄)-alkyl]₂, (g) SO₂NHR^(2a), (h) CF₃, (i) (C₁ -C₇)-alkyl, (j) (C₁ -C₆)-alkoxy, or (k) (C₃-C₇)-cycloalkyl, (l) when R¹¹ and R¹² are bonded to adjacent carbonatoms, they can be joined to form an aryl ring; (m) O(CH₂)_(n+1)O(CH₂)_(s) CH₃, (n) (C₂)_(n+1) O(CH₂)_(s) CH₃, (o) (CH₂)N(R^(2a))₂, (p)CH₂ -N[CH₂ CH₂ ]₂ O, (q) (CH₂)_(n) N[CH₂ CH₂ ]₂ CH₂, (r) CH(OR^(2a))[(C₁-C₇)-alkyl]. (s) CHO, (t) CO₂ R^(2a), (u) CH═CH--R^(2a), (v) CH₂ CR^(2a)═C(R^(2a))₂, (w) (CH₂)_(n) NCOR^(2a), (x) (CH₂)_(n) aryl, or (y)CH(R^(2a))₂ ; Z is:(a) --CO₂ R^(2a), (b) --SO₃ R¹³, (c) --NHSO₂ CF₃, (d)--PO(OR¹³)₂, (e) --SO₂ NHR^(2a), (f) --CONHOR¹³, ##STR92## (h) --CN, (i)--SO₂ NH-heteroaryl, wherein heteroaryl is an unsubstituted,monosubstituted or disubstituted five or six membered aromatic ringwhich can contain from 1 to 3 heteroatoms selected from the groupconsisting of O, N or S and wherein thesubstituents are members selectedfrom the group consisting of: --OH, --SH, --(C₁ -C₄)-alkyl, --(C₁-C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --(C₁-C₄)-alkyl, --NH₂, NH[(C₁ -C₄)-alkyl] and --N[(C₁ -C₄)-alkyl]₂, (j)--CH₂ SO₂ NH-heteroaryl, (k) --SO₂ NH--CO--R¹⁴, (l) --CH₂ SO₂NH--CO--R¹⁴, (m) --CONH--SO₂ R¹⁴, (n) --CH₂ CONH--SO₂ R¹⁴, (o) --NHSO₂NHCO--R¹⁴, (p) --NHCONHSO₂ --R¹⁴, ##STR93## (t) --CONHNHSO₂ CF₃,##STR94## R¹⁴ is (a) aryl, (b) heteroaryl, (c) (C₃ -C₇)-cycloalkyl, or(d) (C₁ -C₇)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of; aryl, heteroaryl, --OH, --SN, (C₁-C₄)-alkyl, --(C₁ -C₄)-alkoxy, --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I,--NO₂, --CO₂ H, CO₂ --(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃H or PO(OH)(O-(C₁ -C₄)-alkyl); (e) (C₁ -C₇)-alkoxy, (f) O(CH₂)_(n+1)O(CH₂)_(s) CH₃, (g) (CH₂)_(n+1) O(CH₂)_(s) CH₃, (h) CH(R^(2a))₂. (i) (C₁-C₆)-polyfluoroalkyl, or (j) NH(C₁ -C₆)-alkyl; R¹⁵ is(a) H, (b) aryl,which is unsubstituted or substituted with 1 or 2 substituents selectedfrom the group consisting of: Cl, Br, I, F --O--(C₁ -C₄)-alkyl, (C₁-C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)--alkyl, --OH,--NH₂, (C₃ -C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl; (c) (C₁ -C₆)-alkyl, (C₂-C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of: aryl, (C₃ -C₇)-cycloalkyl, Cl, Br, I, F, --OH, --NH₂,--NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂ R^(2a),--COOR^(2a), --SO₂ NHR^(2a) ; or (d) an unsubstituted, monosubstitutedor disubstituted aromatic 5 to 6 membered ring which can contain one ortwo heteroatoms selected from the group consisting of N, O, S, andwherein the substituents are members selected from the group consistingof --OH, --SH, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkyloxy, --CF₃, Cl, Br, I, F,or NO₂ ; R¹⁹ is:(a) H, (b) (C₁ -C₆)-alkyl, (c) (C₂ -C₄)-alkenyl, (d) (C₁-C₄)-alkoxy, or (e) benzyl, wherein the phenyl is unsubstituted orsubstituted with a substituent selected from the group consisting of:--NO₂, --NH₂, --OH or --OCH₃ ; R²⁰ is --CN, --NO₂, --CO₂ R^(2a), or--CF₃ ; and R²¹ is:(a) aryl, unsubstituted or substituted with asubstituent selected from Cl, Br, F or I, or (b) (C₁ -C₄)-alkyl, isunsubstituted or substituted with:i) NH₂, ii) NH[(C₁ -C₄)-alkyl], iii)N[(C₁ -C₄)-alkyl]₂, iv) CO₂ H, v) CO₂ (C₁ -C₄)-alkyl, vi) OH, vii) SO₃H, or viii) SO₂ NH₂ ; (c) heteroaryl (d) C₃ -C₇ cycloalkyl.or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1 orits pharmaceutically acceptable salt wherein:R¹ is:(a) (C₁ -C₆)-alkyl or(C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which is unsubstituted orsubstituted with a substituent selected from the group consisting of:i)(C₁ -C₄)-alkylthio, ii) (C₁ -C₄)-alkoxy, iii) CF₃, iv) CF₂ CF₃, or v)(C₃ -C₅)-cycloalkyl, (b) polyfluoro-(C₁ -C₄)-alkyl, or (c) (C₃-C₅)-cyclalkyl; E is:(a) single bond, (b) --S--, or (c) --O--, n is 0,1, or 2; J¹ is (a)--C(═M)--, (b) J¹ and L are connected together to forma 6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b) or (c) J¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom not at J¹, substituted withR^(7a), R^(8a) and R^(8b) ; K¹ is (a)--C(═M)--, or (b) K¹ and L areconnected together to form a 6-carbon aromatic ring substituted withR^(7a), R^(7b), R^(8a) and R^(8b), or (c) K¹ and L are connectedtogether to form a six-membered aromatic ring containing one nitrogenatom substituted with R^(7a), R^(7b) and R^(8b) provided that one andonly one of J¹ and K¹ is --C(═M)--; one of a¹ or b¹ is a double bond instructure Ia provided that when J¹ is --C(═M)-- then b¹ is a double bondand when K¹ is --C(═M)-- then a¹ is a double bond; L is the point ofattachment of the 6-membered fused aromatic ring optionally containingone nitrogen atom; M is O, S or NR¹⁵ ; R² is:(a) H, (b) (C₁ -C₆)-alkyl;R^(2a) is:(a) R², (b) CH₂ aryl, or (c) aryl; R^(2b) is;(a) R^(2a), or(b) C₃ -C₇ cycloalkyl; R^(2c) is:(a) --SO₂ --(C₁ -C₆)-alkyl, (b)--CO--(C₁ -C₆)-alkyl, (c) --SO₂ --(C₃ -C₆)-cycloalkyl, (d) --CO--(C₃-C₆)-cycloalkyl, (e) --SO₂ --(C₁ -C₄)-polyfluoroalkyl, (f) --CO-aryl,(g) --CO-polyfluoroaryl, (h) --CO--(2- or 3-thienyl), (i) --SO₂ -(2- or3-thienyl), (j) --CO--(2-, 3- or 4-pyridyl), (k) --CONH--(C₁ -C₆)-alkyl,(l) --CON[(C₁ -C₆)-alkyl]₂, (m) --CO₂ --(C₁ -C₆)-alkyl, or (n) --CO₂--(C₃ -C₆)-cycloalkyl; R^(7a) and R^(7b) are independently(a) H, (b) (C₁-C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl, (c) Cl, Br, I, F, (d)CF₃, or (e) when R^(7a) and R^(7b) are bonded to adjacent carbon atoms,they can be joined to form a phenyl ring; R^(8a) and R^(8b) areindependently(a) H, (b) aryl-(C₁ -C₄)-alkyl, (c) heteroaryl-(₁-C₄)-alkyl, (d) (C₁ -C₆)-alkyl, is unsubstituted or substituted with asubstituent selected from the group consisting of: --CON(R^(2a))₂,--heteroaryl, --S(O)_(n) --R²¹, --tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂NH-heteroaryl, --SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN,--NR^(2a) COOR²¹, --OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁ -C₄)-dialkylamino, --COOR^(2a),--CONHR^(2a), --O--COR^(2a), aryl, or ##STR95## (e) --CO-aryl, (f) (C₃-C₇)-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i) --OR²¹, (j) --SH, (k)--S(O)_(n) --(C₁ -C₄)-alkyl, (l) --COR^(2a), (m) --CO₂ H, (n) --SO₃ H,(o) --NR^(2a) R²¹, (p) --NR^(2a) COR²¹, (q) --NR^(2a) COOR²¹, (r) --SO₂NR^(2a), (s) --SO₂ NR² R^(2a), (t) --NO₂, (u) --NHSO₂ CF₃, (v)--CONR^(2a) R²¹, (w) --(C₁ -C₄)-polyfluoroalkyl, (x) --COOR², (y) --SO₃H, (z) --N(R^(2a))SO₂ R²¹, (aa) --NR^(2a) CONR^(2b) R²¹, (bb)--OC(═O)NR²¹ R^(2a), (cc) --aryl, (dd) --NHSO₂ CF₃, (ee) --SO₂NH-heteroaryl, (ff) --SO₂ NHCOR²¹, (gg) --CONHSO₂ R²¹, (hh) --PO(OR²)₂,(ii) -tetrazol-5-yl, (jj) --CONH(tetrazol-5-yl), (kk) --SO₂ NHCH, (ll)-heteroaryl, ##STR96## --X¹ --X² --X³ --X⁴ -- is: (a) --Y--CR¹¹ --CR¹²--CZ--, (b) --CR¹¹ --Y--CR¹² --CZ--, (c) --CR¹¹ --CR¹² --Y--CZ--, (d)--Y--CR¹¹ --CZ--CR¹² --, (e) --CR¹¹ --Y--CZ--CR¹² --, or (f) --CR¹¹--CR¹² --CZ--Y--; Y is: O, S, SO, or SO₂ ; R⁹ and R¹⁰ are eachindependently:(a) H, (b) Cl, Br, I, F, (c) NO₂, (d) (C₁ -C₆)-alkyl, (e)(C₁ -C₆)-acyloxy, (f) (C₃ -C₆)-cycloalkyl, (g) (C₁ -C₆)-alkoxy, (h)--NHSO₂ R^(2a), (k) hydroxy-(C₁ -C₄)-alkyl, (j) (C₁ -C₄ -alkyl-aryl, (k)S(O)_(n) --(C₁ -C₄)-alkyl, (n) NR^(2a) R^(2a), (q) CF₃, (r) --SO₂NHR^(2a), (s) furyl, (t) aryl, wherein aryl is phenyl or naphthyl,unsubstituted or substituted with one or two substituents selected fromthe group consisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy,NO₂, CF₃, (C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁-C₄)-alkyl]₂, --CO₂ H, or --CO₂ --(C₁ -C₄)-alkyl, or (u) when R⁹ and R¹⁰are bonded to adjacent carbon atoms, they can be joined to form an arylring; R¹¹ and R¹² are independently:(a) H, (b) Cl, Br, I, F, (c) NO₂,(d) NH₂, (e) NH[(C₁ -C₄)-alkyl], (f) N[(C₁ -C₄)-alkyl]₂, (g) SO₂NHR^(2a), (h) CF₃, (i) (C₁ -C₇)-alkyl, (j) (C₁ -C₆)-alkoxy, (k) (C₃-C₇)-cycloalkyl, (l) when R¹¹ and R¹² are bonded to adjacent carbonatoms, they can be joined to form an aryl ring, (m) (CH₂)_(n+1)O(CH₂)_(s) CH₃, (n) (CH₂)_(n+1) O(CH₂)_(s) CH₃, (o) (CH₂)N(R^(2a))₂, (p)CH₂ --N[CH₂ CH₂ ]₂ O, (q) (CH₂)_(n) N[CH₂ CH₂ ]₂ CH₂, (r)CH(OR^(2a))[(C₁ -C₇)-alkyl], (s) CHO, (t) CO₂ R^(2a), (u) CH═CH--R^(2a),(v) CH₂ CR^(2a) ═C(R^(2a))₂, (w) (CH₂)_(n) NCOR^(2a), (x) (C₁-C₄)-alkyl-aryl, or (y) CH(R^(2a))₂ ; Z is:(a) --CO₂ R^(2a), (b) --NHSO₂CF₃, (c) --SO₂ NHR^(2a), (d) --CN, (e) --SO₂ NH-heteroaryl, whereinheteroaryl is an unsubstituted, monosubstituted or disubstituted five orsix membered aromatic ring which can optionally contain from 1 to 3heteroatoms selected from the group consisting of O, N or S and whereinthe substituents are members selected from the group consisting of --OH,--SH, --(C₁ -C₄)-alkyl, --(C₁ -C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂,--CO₂ H, --CO₂ --C₁ -C₄ -alkyl, --NH₂, NH[(C₁ -C₄)-alkyl] and --N[(C₁-C₄ -alkyl]₂, (f) --1H-tetrazol-5-yl. (g) --CH₂ --1H-tetrazol-5-yl, (h)--CONH--1H-tetrazol-5-yl, or (i) --SO₂ NHCOR¹⁴ ; R¹⁴ is(a) aryl, (b)heteroaryl, (c) (C₃ -C₇)-cycloalkyl, or (d) (C₁ -C₇)-alkyl,unsubstituted or substituted with a substituent selected from the groupconsisting of: aryl, heteroaryl, --OH, --SH, (C₁ -C₄)-alkyl, --(C₁-C₄)-alkoxy, --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, CO₂--(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃ H or PO(OH)(O-(C₁-C₄)-alkyl); (e) (C₁ -C₇)-alkoxy, (f) O(CH₂)_(n+1) O(CH₂)_(s) CH₃, (g)(CH₂)_(n+1) O(CH₂)₂ CH₃, (h) CH(R^(2a))₂, or, (i) --NH--(C₁ -C₆)-alkyl;R¹⁵ is:(a) H, (b) aryl, is unsubstituted or substituted with 1 or 2substituents selected from the group consisting of Cl, Br, I, F,--O--(C₁ -C₄)-alkyl, (C₁ -C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a),--S--(C₁ -C₄)-alkyl, --OH, --NH₂, (C₃ -C₇)-cycloalkyl, (C₃-C₁₀)-alkenyl; (c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyleach of which is unsubstituted or substituted with one or moresubstituents selected from the group consisting of: aryl, (C₃-C₇)-cycloalkyl, Cl, Br, I, F, --OH, --NH[(C₁ -C₄)-alkyl], --N[(C₁-C₄)-alkyl]₂, --NH--SO₂ R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or (d) anunsubstituted, monosubstituted or disubstituted aromatic 5 or 6 memberedring which contains one or two heteroatoms selected from the groupconsisting of N, O, S, and wherein the substituents are members selectedfrom the group consisting of --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkyloxy --CF₃, Cl, Br, I, F, or NO₂ ; R²¹ is:(a) aryl,unsubstituted or substituted with a substituent selected from Cl, Br, For I, or (b) (C₁ -C₄)alkyl which is unsubstituted or substituted with:i)NH₂, ii) NH[(C₁ -C₄)-alkyl], iii) N[(C₁ -C₄)-alkyl]₂, iv) CO₂ H, v) CO₂(C₁ -C₄)-alkyl,vi) OH, vii) SO₃ H, or viii) SO₂ NH₂, (c) heteroaryl, or(d) (C₃ -C₇)-cycloalkyl.
 3. The compound of claim 1 or itspharmaceutically acceptable salt wherein:R¹ is:(a) (C₁ -C₆)-alkyl (C₂-C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which is unsubstituted orsubstituted with a substituent selected from the group consisting of:i)(C₁ -C₄)-alkylthio, ii) (C₁ -C₄)-alkoxy, iii) CF₃, iv) CF₂ CF₃, or v)(C₃ -C₅)-cycloalkyl, or (b) (C₁ -C₄)-polyfluoroalkyl; E is a singlebond; n is 0 to 2; J¹ and L are connected together to form a 6-carbonaromatic ring substituted with R^(7a), R^(7b), R^(8a) and R^(8b) ; or J¹and L are connected together to form a 6-membered aromatic ringcontaining one nitrogen atom not at J¹, substituted with R^(7a), R^(8a)and R^(8b) ; K¹ is --C(═M)--; a¹ is a double bond; L is the point ofattachment of the 6-membered fused aromatic ring optionally containingone nitrogen atom; M is O, or NR¹⁵ ; R² is:(a) H, (b) (C₁ -C₆)-alkyl, or(c) (C₁ -C₆)-alkyl; R^(2a) is:(a) R², (b) benzyl, or (c) phenyl; R^(2b)is:(a) R^(2a), or (b) (C₃ -C₇) cycloalkyl; R^(2c) is:(a) --SO₂ --(C₁-C₆)-alkyl, (b) --CO--(C₁ -C₆)-alkyl, (c) --SO₂ --(C₃ -C₆)-cycloalkyl,(d) --CO--(C₃ -C₆)-cycloalkyl, (e) --SO₂ --(C₁ -C₄)-polyfluoroalkyl, (f)--CO-aryl, (g) --CO-polyfluoroaryl, (h) --Co-(2- or 3-thienyl), (i)--SO₂ -(2- or 3-thienyl), (j) --CO-(2-, 3- or 4-pyridyl), (k) --CONH-(C₁-C₆)-alkyl, (l) --CON[(C₁ -C₆)-alkyl]₂, (m) --CO₂ -(C₁ -C₆)-alkyl, or(n) --CO₂ -(C₃ -C₆)-cycloalkyl; R^(7a) and R^(7b) are independently;(a)H, (b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl. (c) Cl, Br,I, F, (d) CF₃, or (e) when R^(7a) and R^(7b) are bonded to adjacentcarbon atoms, they can be joined to form a phenyl ring; R^(8a) andR^(8b) are independently:(a) H, (b) aryl-(C₁ -C₄)-alkyl, (c)heteroaryl-(C₁ -C₄)-alkyl, (d) (C₁ -C₆)-alkyl, unsubstituted orsubstituted with a substituent selected from the group consisting of:--CON(R^(2a))₂, -heteroaryl, --S(O)_(n) -R²¹, -tetrazol-5-yl, --CONHSO₂R²¹, --SO₂ NH-heteroaryl, --SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂,--SO₂ NH--CN, --NR^(2a) COOR²¹, --OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy,(C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁ -C₄)-dialkylamino,--COOR^(2a), --CONHR^(2a), --O--COR^(2a), aryl,or ##STR97## (e)--CO-aryl, (f) (C₃ -C₇)-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i)--OR²¹, (j) --SH, (k) --S(O)_(n) --(C₁ -C₄)-alkyl, (l) --COR^(2a), (m)--CO₂ H, (n) --SO₃ H, (o) --NR^(2a) R²¹, (p) --NR^(2a) COR²¹, (q)--NR^(2a) COOR²¹, (r) --SO₂ NR^(2a),(s) --SO₂ NR² R^(2a), (t) --NO₂, (u)--NHSO₂ CF₃, (v) --CONR^(2a) R²¹, (w) --(C₂ -C₄)-polyfluoroalkyl, (x)--COOR², (y) --SO₃ H, (z) --N(R^(2a))SO₂ R²¹, (aa) --NR^(2a) CONR^(2b)R²¹, (bb) --OC(═O)NR²¹ R^(2a), (cc) -aryl, (dd) --NHSO₂ CF₃, (ee) --SO₂NH-heteroaryl, (ff) --SO₂ NHCOR²¹, (gg) --CONHSO₂ R²¹, (hh) --PO(OR²)₂,(ii) -tetrazol-5-yl, (jj) --CONH(tetrazol-5-yl), (kk) --SO₂ NHCN, (ll)-heteroaryl, ##STR98## --X¹ --X² --X³ --X⁴ -- is; (a) --Y--CR¹¹ --CR¹²--CZ--, (b) --CR¹¹ --Y--CR¹² --DZ--, (c) --CR¹¹ --CR¹² --Y--CZ--, (d)--Y--CR¹¹ --CZ--CR¹² --, (e) --CR¹¹ --Y--CZ--CR¹² --, or (f) --CR¹¹--CR¹² --CZ--Y--; Y is: O or S; n is: 0 to 2; R¹¹ and R¹² areindependently:(a) H, (b) Cl, Br, I, F, (c) NH₂, (d) NH[(C₁ -C₄)-alkyl],(e) N[(C₁ -C₄)-alkyl]₂ (f) SO₂ NHR^(2a), (g) CF₃, (h) (C₁ -C₇)-alkyl,(i) (C₁ -C₄)-alkoxy, or (j) (C₃ -C₆)-cycloalkyl; Z is:(a) --CO₂ R^(2a),(b) --NHSO₂ CF₃, (c) --SO₂ NHR¹⁴, (d) --1H-tetrazol-5-yl, (e) --SO₂NHCOR¹⁴, or (f) --NHSO₂ R¹⁴ ; R¹⁴ is (a) aryl,(b) heteroaryl, (c) (C₃-C₇)-cycloalkyl, (d) (C₁ -C₄)-alkyl, unsubstituted or substituted with asubstituted selected from the group consisting of aryl as defined above,heteroaryl as defined above, --OH, --SH, (C₁ -C₄)-alkyl, --(C₁-C₄)-alkoxy, --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, CO₂--(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃ H, PO(OH)(O-(C₁-C₄)-alkyl); (e) (C₁ -C₇)-alkoxy, (f) O(CH₂)_(n+1) O(CH₂)_(s) CH₃, (g)(CH₂)_(n+1) O(CH₂)_(s) CH₃, (h) CH(R^(2a))₂, (i) (C₁-C₆)-polyfluoroalkyl, or (j) --NH(C₁ -C₆)-alkyl; R¹⁵ is:(a) H, (b) aryl,unsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of: Cl, Br, I, F --O--(C₁ -C₄)-alkyl, (C₁ -C₄)-alkyl,--NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl, --OH, --NH₂, (C₃--C₇)-cycloalkyl, (C₃ --C₁₀)-alkenyl; (c) (C₁ -C₆)-alkyl, (C₂-C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of aryl as defined above, (C₃ -C₆)-cyclalkyl, Cl, Br, I, F,--OH, --NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or (d) an unsubstituted,monosubstituted or disubstituted aromatic 5 or 6 membered ring which cancontain one or two heteroatoms selected from the group consisting of N,O, S, and wherein the substituents are members selected from the groupconsisting of: --OH, --SH, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkyloxy, --CF₃, Cl,Br, I, F, or NO₂ ; and R²¹ is(a) aryl, unsubstituted or substituted witha substituent selected from Cl, Br, F, or I, or (b) (C₁ -C₄)-alkyl whichis unsubstituted of substituted with:i) NH₂, ii) NH[(C₁ -C₄)-alkyl],iii) N[(C₁ -C₄)-alkyl]₂, iv) CO₂ H, v) CO₂ (C₁ -C₄)-alkyl, vi) OH, vii)SO₃ H, viii) SO₂ NH₂, (c) heteroaryl, or (d) (C₃ -C₇)-cycloalkyl.
 4. Thecompound of claim 1 of structural formula ##STR99## or apharmaceutically acceptable salt thereof.
 5. The compound of claim 1 orits pharmaceutically acceptable salt in which the structural formula is##STR100## wherein R¹ is: ethyl, n-propyl, n-butyl or n-pentyl;R^(2c)is: (a) --SO₂ --(C₁ -C₆)-alkyl, (b) --CO--(C₁ -C₆)-alkyl, (c) --SO₂--(C₃ -C₆)-cycloalkyl, (d) --CO--(C₃ -C₆)-cycloalkyl, (e) --SO₂ --(C₁-C₄)-polyfluoroalkyl, (f) --CO-aryl; (g) --CO-polyfluoroaryl, (h)--CO--(2- or 3-thienyl), (i) --SO₂ --(2- or 3-thienyl), (j) --CO--(2-,3- or 4-pyridyl),(k) --CONH-(C₁ -C₆)-alkyl, (l) --CON[(C₁ -C₆)-alkyl]₂,(m) --CO₂ -(C₁ -C₆)-alkyl, or (n) --CO₂ -(C₃ -C₆)-cycloalkyl; R^(8b)is:N(n-butyl)CO-phenyl, N(pentyl)CO-phenyl, N(benzyl))CO-phenyl,N(benzyl)CO₂ -isobutyl, N(pentyl)CO-4-pyridyl,N(pentyl)CO-(4-chlorophenyl), N(n-butyl)CO-(4-fluorophenyl),N(methyl)CO₂ -isobutyl, isopropyl, N(benzyl)CON(methyl)(ethyl), or##STR101## R¹² is: H, (C₁ -C₆)-alkyl, benzyl, or ##STR102## Z is: (a)CO₂ R², (b) 1H-tetrazol-5-yl, (c) CONHSO₂ R¹⁴, (d) SO₂ NHR¹⁴, (e) NHSO₂R¹⁴, (f) SO₂ NHCOR¹⁴, or (g) NHSO₂ CF₃ ; and R¹⁴ is:(a) phenyl, (b) (C₁-C₆)-alkyl, (c) (C₁ -C₆)-alkoxy, (d) CH₂ phenyl, (f) ##STR103## (g) (C₃-C₇)-cycloalkyl, (h) (C₁ -C₃)-alkyl-(C₃ -C₆)-cycloalkyl, (i) (CH₂)₅ NH₂,(j) O(CH₂)_(n+1) O(CH₂)_(s) CH₃. (k) (CH_(2n+1) O(CH₂)_(s) CH₃, or (j)--NH(C₁ -C₆)-alkyl.
 6. A pharmaceutical composition useful in thetreatment of hypertension which comprises a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1.7. A method of treating hypertension which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa compound of claim
 1. 8. An ophthalmological formulation for thetreatment of ocular hypertension comprising an ophthalmologicallyacceptable carrier and an effective ocular antihypertensive amount of acompound of claim
 1. 9. A method of treating ocular hypertensioncomprising topical ocular administration to a patient in need of suchtreatment of an effective ocular antihypertensive amount of a compoundof claim
 1. 10. A compound of structural formula I ##STR104## or itspharmaceutically acceptable salt thereof. wherein:R¹ is: ethyl,n-propyl, n-butyl or n-pentyl; --X¹ --X² --X³ --X⁴ -- is:(a) --Y--CR¹¹--CR¹² --CZ, (b) --CR¹¹ --Y--CR¹² --CZ--, or (c) --CR¹¹ --CR¹² --Y--CZ;Y is: O or S; R^(8b) is:(a) H, (b) CH₃, (c) N(CH₃)(CO₂ CH₃), (d)N(CH₃)(CO₂ iBu), (e) N(Bz)(CO₂ iBu), (f) N(Bz)(CO₂ Bu), (g) N(Boz)(nPn),(h) N(Boz)(Bz), (i) N(Bz)(CO₂ CH₃), (j) N(Bz)]CON(CH₃)(Et)], (k)NHCOnPn, (l) NHCONHEt, or (m) NHCONHiPr; Z is:(a) tetrazol-5-yl, (b) SO₂NHCOPh, (c) SO₂ NHCOCF₃, (d) SO₂ NHCOcyPr, (e) SO₂ NHCO₂ Bu, (f) SO₂NHCOnPn, (g) SO₂ NHCOCH₂ OBu, or (h) SO₂ NHCO₂ (CH₂)₂ OCH₃ ; and R¹¹ andR¹² are:(a) both H, (b) when R¹¹ and R¹² are bonded to adjacent carbonatoms, they can be joined to form a phenyl ring; or (c) when R¹¹ is H,R¹² is (C₁ -C₆)-alkyl, benzyl or CH₂ --[CH₂ CH₂ ]₂ O.
 11. A compound orits pharmaceutically acceptable salt in which the structural formula is:##STR105## and wherein R¹ is: ethyl, n-propyl, n-butyl or n-pentyl;R²is: H or (C₁ -C₆)-alkyl; R^(2c) is:(a) --SO₂ --(C₁ -C₆)-alkyl, (b)--CO--(C₁ -C₆)-alkyl, (c) --SO₂ -(C₃ -C₆)-cycloalkyl, (d) --CO--(C₃--C₆)-cycloalkyl, (e) --SO₂ -(C₁ -C₄)-polyfluoroalkyl, (f) --CO-aryl,(g) --CO-polyfluoroaryl, (h) --CO-(2- or 3-thienyl), (i) --SO₂ -(2- or3-thienyl), (j) --CO-(2-, 3- or 4- pyridyl), (k) --CONH-(C₁ -C₆)-alkyl,(l) --CON[(C₁ -C₆)-alkyl]₂, (m) --CO₂ -(C₁ -C₆)-alkyl, or (n) --CO₂ -(C₃-C₆)-cycloalkyl; n is: 0, 1 or 2; s is: 0 to 5; R^(8b)is:N(n-butyl)CO-phenyl, N(pentyl)CO-phenyl, N(benzyl))CO-phenyl,N(benzyl)CO₂ -isobutyl, N(pentyl)CO-4-pyridyl,N(pentyl)CO-(4-chlorophenyl), N(n-butyl)CO-(4-fluorophenyl),N(methyl)CO₂ -isobutyl, isopropyl, N(benzyl)CON(methyl)(ethyl), or##STR106## R¹² is: H, (C₁ -C₆)-alkyl, benzyl, or ##STR107## Z is: (a)CO₂ R², (b) 1H-tetrazol-5-yl, (c) CONHSO₂ R¹⁴, (d) SO₂ NHR¹⁴, (e) NHSO₂R¹⁴, (f) SO₂ NHCOR¹⁴, or (g) NHSO₂ CF₃ ; and R¹⁴ is:(a) phenyl, (b) (C₁-C₆)-alkyl, (c) (C₁ -C₆)-alkoxy, (d) CH₂ phenyl, (f) ##STR108## (g) (C₃-C₇)-cycloalkyl, (h) (C₁ -C₃)-alkyl-(C₃ -C₆)-cycloalkyl, (i) (CH₂)₅ NH₂,(j) O(CH₂)_(n+1) O(CH₂)_(s) CH₃, (k) (CH₂)_(n+1) O(CH₂)_(s) CH₃, or (j)--NH(CH₁ -C₆)-alkyl.